Pyrrolidin-2-one and piperidin-2-one derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors

ABSTRACT

The N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein
         n is 1 or 2;   L represents a C 1-3 alkyl linker optionally substituted with one or two substituents selected from C 1-4 alkyl, C 1-3 alkyloxy-C 1-4 alkyl-, hydroxy-C 1-4 alkyl, hydroxy, C 1-3 alkyloxy- or phenyl-C 1-4 alkyl;   M represents a direct bond or a C 1-3 alkyl linker optionally substituted with one or two substituents selected from hydroxy, C 1-4 alkyl or C 1-4 alkyloxy;   R 1  and R 2  each independently represent hydrogen, halo, cyano, hydroxy,   C 1-4 alkyl optionally substituted with halo,   C 1-4 alkyloxy- optionally substituted with one or where possible two or three substituents selected from hydroxy, Ar 1  and halo;   or R 1  and R 2  taken together with the phenyl ring to which they are attached form naphtyl or 1,3-benzodioxolyl, wherein said naphtyl or 1,3-benzodioxolyl are optionally substituted with halo;   R 3  represents hydrogen, halo, C 1-4 alkyl, C 1-4 alkyloxy-, cyano or hydroxy;   R 4  represents hydrogen, halo, C 1-4 alkyl, C 1-4 alkyloxy-, cyano or hydroxy;   R 5  represents hydrogen, C 1-4 alkyl or Ar 2 —C 1-4 alkyl-;   R 6  represents hydrogen, halo, C 1-4 alkyl or C 1-4 alkyoxy-;   Ar 1  and Ar 2  each independently represent phenyl or naphtyl wherein said phenyl and naphtyl are optionally substituted with C 1-4 alkyl, C 1-4 alkyloxy-, or phenyl-C 1-4 alkyl;
 
for use as a medicine.

The metabolic syndrome is a disease with increasing prevalence not onlyin the Western world but also in Asia and developing countries. It ischaracterised by obesity in particular central or visceral obesity, type2 diabetes, hyperlipidemia, hypertension, arteriosclerosis, coronaryheart diseases and eventually chronic renal failure (C. T. Montague etal. (2000), Diabetes, 49, 883-888).

Glucocorticoids and 11β-HSD1 are known to be important factors indifferentiation of adipose stromal cells into mature adipocytes. In thevisceral stromal cells of obese patients, 11β-HSD1 mRNA level isincreased compared with subcutaneous tissue. Further, adipose tissueover-expression of 11β-HSD1 in transgenic mice is associated withincreased corticosterone levels in the adipose tissue, visceral obesity,insulin sensitivity, Type 2 diabetes, hyperlipidemia and hyperphagia (H.Masuzaki et al (2001), Science, 294, 2166-2170). Therefore, 11β-HSD1 ismost likely be involved in the development of visceral obesity and themetabolic syndrome.

Inhibition of 11β-HSD1 results in a decrease in differentiation and anincrease in proliferation of adipose stromal cells. Moreover,glucocorticoid deficiency (adrenalectomy) enhances the ability ofinsulin and leptin to promote anorexia and weight loss, and this effectis reversed by glucocorticoid administration (P. M. Stewart et al(2002), Trends Endocrin. Metabol, 13, 94-96). These data suggest thatenhanced reactivation of cortisone by 11β-HSD1 may exacerbate obesityand it may be beneficial to inhibit this enzyme in adipose tissue ofobese patients.

Obesity is also linked to cardiovascular risks. There is a significantrelationship between cortisol excretion rate and HDL cholesterol in bothmen and women, suggesting that glucocorticoids regulate key componentsof cardiovascular risk. In analogy, aortic stiffness is also associatedwith visceral adiposity in older adults.

Glucocorticoids and Glaucoma

Glucocorticoids increase the risk of glaucoma by raising the intraocularpressure when administered exogenously and in certain conditions ofincreased production like in Cushing's syndrome. Corticosteroid-inducedelevation of intra ocular pressure is caused by increased resistance toaqueous outflow due to glucocorticoid induced changes in the trabecularmeshwork and its intracellular matrix. Zhou et al. (Int J Mol Med (1998)1, 339-346) also reported that corticosteroids increase the amounts offibronectin as well as collagen type I and type IV in the trabecularmeshwork of organ-cultured bovine anterior segments.

11β-HSD1 is expressed in the basal cells of the corneal epithelium andthe non-pigmented epithelial cells. Glucocorticoid receptor mRNA wasonly detected in the trabecular meshwork, whereas in the non-pigmentedepithelial cells mRNA for the glucocorticoid-, mineralocorticoidreceptor and 11β-HSD1 was present. Carbenoxolone administration topatients resulted in a significant decrease in intra-ocular pressure (S.Rauz et al. (2001), Invest. Ophtalmol. Vis. Science, 42, 2037-2042),suggesting a role for HSD1-inhibitors in treating glaucoma.

Accordingly, the underlying problem to be solved by the presentinvention was to identify potent 11β-HSD inhibitors, with a highselectivity for 11β-HSD1, and the use thereof in treating pathologiesassociated with excess cortisol formation such as obesity, diabetes,obesity related cardiovascular diseases, and glaucoma. As shownhereinbelow, the 3-substituted 2-pyrrolidinone derivatives of formula(I) were found to be useful as a medicine, in particular in themanufacture of a medicament for the treatment of pathologies associatedwith excess cortisol formation.

Blommaert A. et al. (Heterocycles (2001), 55(12), 2273-2278) providesthe preparation of piperidine- and pyrrolidinone-like polymer supported(R)-phenylglycinol-derived scaffolds and in particular discloses2-Pyrrolidinone,1-[(1R)-2-hydroxy-1-phenylethyl]-3-methyl-3-(phenylmethyl)- and2-Pyrrolidinone, 1-[(1R)-2-hydroxy-1-phenylethyl]-3-(phenylmethyl)-,(3R).

Bausanne I. et al. (Tetrahedron: Assymetry (1998), 9(5), 797-804)provides the preparation of 3-substituted pyrrolidinones viaα-alkylation of a chiral non-racemic γ-lacton and in particulardiscloses 1-(2-hydroxy-1-phenylethyl)-3-benzylpyrrolidin-2-one.

US 2001/034343; U.S. Pat. No. 6,211,199; U.S. Pat. No. 6,194,406; WO97/22604 and WO 97/19074 are a number of patent applications filed byAventis Pharmaceuticals Inc. providing4-(1H-benzimidazol-2-yl)[1,4]diazepanes useful for the treatment ofallergic diseases. In these applications the 3-substitutedpyrrolidinones of the present invention are disclosed as intermediatesin the synthesis of said 4-(1H-benzimidazol-2-yl)[1,4]diazepanes. Theseapplications in particular disclose; 2-Pyrrolidinone,3-[(4-fluorophenyl)methyl]-1-[(1S)-1-phenylethyl]- and 2-Pyrrolidinone,3-[(4-fluorophenyl)methyl]-1-[(1R)-1-phenylethyl]-.

The general synthesis and absolute configuration of diastereomeric3-substituted 1-[1′-(S)-phenylethyl]-2-pyrrolidinones is provided byNikiforov T. T. and Simeonov E. E. in Doklady Bolgarskoi Academii Nauk(1986), 39(3), 73-76. It exemplifies the synthesis of 2-Pyrrolidinone,3-methyl-3-[(4-methylphenyl)methyl]-1-(1-phenylethyl)-, [S—(R*, R*)];2-Pyrrolidinone, 3-methyl-3-[(4-methylphenyl)methyl]-1-(1-phenylethyl)-,[S—(R*, S*)]; 2-Pyrrolidinone,3-[(4-methylphenyl)methyl]-1-(1-phenylethyl)-, [S—(R*, R*)] and2-Pyrrolidinone, 3-[(4-methylphenyl)methyl]-1-(1-phenylethyl)-, [S—(R*,S*)].

However, in none of the cited documents the therapeutic application ofthe 3-substituted 2-pyrrolidinone derivatives of the present inventionhas been disclosed. Accordingly, in a first aspect this inventionconcerns compounds of formula (I)

the N-oxide forms, the pharmaceutically acceptable addition salts andthe stereochemically isomeric forms thereof, wherein

-   -   n is 1 or 2;    -   L represents a C₁₋₃alkyl linker optionally substituted with one        or two substituents selected from C₁₋₄alkyl,        C₁₋₃alkyloxy-C₁₋₄alkyl-, hydroxy-C₁₋₄alkyl, hydroxy,        C₁₋₃alkyloxy- or phenyl-C₁₋₄alkyl;    -   M represents a direct bond or a C₁₋₃alkyl linker optionally        substituted with one or two substituents selected from hydroxy,        C₁₋₄alkyl or C₁₋₄alkyloxy;    -   R¹ and R² each independently represent hydrogen, halo, cyano,        hydroxy,    -   C₁₋₄alkyl optionally substituted with halo,    -   C₁₋₄alkyloxy- optionally substituted with one or where possible        two or three substituents selected from hydroxy, Ar¹ and halo;    -   or R¹ and R² taken together with the phenyl ring to which they        are attached form naphtyl or 1,3-benzodioxolyl, wherein said        naphtyl or 1,3-benzodioxolyl are optionally substituted with        halo;    -   R³ represents hydrogen, halo, C₁₋₄alkyl, C₁₋₄alkyloxy-, cyano or        hydroxy;    -   R⁴ represents hydrogen, halo, C₁₋₄alkyl, C₁₋₄alkyloxy-, cyano or        hydroxy;    -   R⁵ represents hydrogen, C₁₋₄alkyl or Ar²—C₁₋₄alkyl;    -   R⁶ represents hydrogen, halo, C₁₋₄alkyl or C₁₋₄alkyoxy-;    -   Ar¹ and Ar² each independently represent phenyl or naphtyl        wherein said phenyl and    -   naphtyl are optionally substituted with C₁₋₄alkyl,        C₁₋₄alkyloxy-, or phenyl-C₁₋₄alkyl;        for use as a medicine.

As used in the foregoing definitions and hereinafter, halo is generic tofluoro, chloro, bromo and iodo; C₁₋₃alkyl defines straight and branchedchain saturated hydrocarbon radicals having from 1 to 4 carbon atomssuch as, for example, methyl, ethyl, propyl, 1-methylethyl and the like;C₁₋₄alkyl defines straight and branched chain saturated hydrocarbonradicals having from 1 to 4 carbon atoms such as, for example, methyl,ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylethyland the like; C₁₋₄alkyloxy defines straight or branched saturatedhydrocarbon radicalshaving form 1 to 3 carbon atoms such as methoxy,ethoxy, propyloxy, 1-methylethyloxy and the like; C₁₋₄alkyloxy definesstraight or branched saturated hydrocarbon radicals having form 1 to 4carbon atoms such as methoxy, ethoxy, propyloxy, butyloxy,1-methylethyloxy, 2-methylpropyloxy and the like.

The pharmaceutically acceptable addition salts as mentioned hereinaboveare meant to comprise the therapeutically active non-toxic acid additionsalt forms, which the compounds of formula (I), are able to form. Thelatter can conveniently be obtained by treating the base form with suchappropriate acid. Appropriate acids comprise, for example, inorganicacids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid;sulfuric; nitric; phosphoric and the like acids; or organic acids suchas, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic,oxalic, malonic, succinic (i.e. butanedioic acid), maleic, fumaric,malic, tartaric, citric, methanesulfonic, ethanesulfonic,benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, pamoic and the like acids.

The pharmaceutically acceptable addition salts as mentioned hereinaboveare meant to comprise the therapeutically active non-toxic base additionsalt forms which the compounds of formula (I), are able to form.Examples of such base addition salt forms are, for example, the sodium,potassium, calcium salts, and also the salts with pharmaceuticallyacceptable amines such as, for example, ammonia, alkylamines,benzathine, N-methyl-D-glucamine, hydrabamine, amino acids, e.g.arginine, lysine.

Conversely said salt forms can be converted by treatment with anappropriate base or acid into the free acid or base form.

The term addition salt as used hereinabove also comprises the solvateswhich the compounds of formula (I), as well as the salts thereof, areable to form. Such solvates are for example hydrates, alcoholates andthe like.

The term stereochemically isomeric forms as used hereinbefore definesthe possible different isomeric as well as conformational forms whichthe compounds of formula (I), may possess. Unless otherwise mentioned orindicated, the chemical designation of compounds denotes the mixture ofall possible stereochemically and conformationally isomeric forms, saidmixtures containing all diastereomers, enantiomers and/or conformers ofthe basic molecular structure. All stereochemically isomeric forms ofthe compounds of formula (I), both in pure form or in admixture witheach other are intended to be embraced within the scope of the presentinvention.

The N-oxide forms of the compounds of formula (I), are meant to comprisethose compounds of formula (I) wherein one or several nitrogen atoms areoxidized to the so-called N-oxide.

An interesting group of compounds consists of those compounds of formula(I) wherein one or more of the following restrictions apply:

-   -   (i) n is 1 or 2; in particular n is 1    -   (ii) L represents a C₁₋₃alkyl linker optionally substituted with        one or two substituents selected from C₁₋₄alkyl,        C₁₋₃alkyloxy-C₁₋₄alkyl-, hydroxy-C₁₋₄alkyl, hydroxy,        C₁₋₃alkyloxy- or phenyl-C₁₋₄alkyl; in particular L represents a        C₁-linker optionally substituted with C₁₋₄alkyl; preferably L        represents a C₁-linker substituted with C₁₋₄alkyl, more        preferably a C₁-linker substituted with methyl;    -   (iii) M represents a direct bond or a C₁₋₂alkyl optionally        substituted with one or two substituents selected from hydroxy,        C₁₋₄alkyl or C₁₋₄alkyloxy-; in particular M represents a        C₁₋₂alkyl optionally substituted with one or two substituents        selected from hydroxy, C₁₋₄alkyl or C₁₋₄alkyloxy-; preferably M        represents a C₁-linker optionally substituted with C₁₋₄alkyl;    -   (iv) R¹ represents hydrogen, hydroxy, halo, C₁₋₄alkyl,        C₁₋₄alkyloxy-, or C₁₋₄alkyloxy substituted with halo;    -   (v) R² represents hydrogen, halo, C₁₋₄alkyl, C₁₋₄alkyloxy- or        Ar¹—C₁₋₄alkyloxy-;    -   (vi) R³ represents hydrogen, halo, C₁₋₄alkyl, C₁₋₄alkyloxy- or        cyano;    -   (vii) R⁴ represents hydrogen, halo, C₁₋₄alkyl or C₁₋₄alkyloxy-;    -   (viii) R⁵ represents hydrogen, C₁₋₄alkyl or Ar²—C₁₋₄alkyl; in        particular hydrogen;    -   (ix) R⁶ represents hydrogen, halo, or C₁₋₄alkyloxy; in        particular hydrogen, chloro, fluoro, bromo or methoxy;    -   (x) Ar¹ represents phenyl;    -   (xi) Ar² represents phenyl or naphtyl;

Another group of compounds consists of those compounds of formula (I)wherein one or more of the following restrictions apply:

-   -   (i) n is 1;    -   (ii) L represents a C₂₋₃alkyl linker optionally substituted with        one or two substituents selected from C₁₋₄alkyl,        C₁₋₃alkyloxy-C₁₋₄alkyl-, hydroxy-C₁₋₄alkyl, hydroxy,        C₁₋₃alkyloxy- or phenyl-C₁₋₄alkyl;    -   (iii) M represents a C₂₋₃alkyl linker optionally substituted        with one or two substituents selected from hydroxy, C₁₋₄alkyl or        C₁₋₄alkyloxy;    -   (iv) R⁵ represents Ar²—C₁₋₄alkyl;    -   (v) R⁶ represents halo, C₁₋₄alkyl or C₁₋₄alkyloxy-.

Another group of interesting compounds consists of those compounds offormula (I) wherein one or more of the following restrictions apply:

-   -   (i) n is 1;    -   (ii) L represents a C₁₋₃alkyl linker optionally substituted with        ethyl or methyl, in particular L represents a C₁-linker        substituted with ethyl or methyl;    -   (iii) M represents a C₁-linker optionally substituted methyl;    -   (iv) R¹ and R² represent C₁₋₄alkyloxy, in particular methoxy or        R¹ and R² taken together with the phenyl ring to which they are        attached form 1,3-benzodioxolyl substituted with halo;    -   (v) R³ represents chloro, fluoro, methyl or hydrogen;    -   (vi) R⁴ represents chloro, fluoro or methyl;    -   (vii) R⁵ represents hydrogen;    -   (viii) R⁶ represents hydrogen.

A further group of compounds according to the present invention arethose compounds wherein R⁶ is at the para position, L represents aC₂-alkyl linker and M represents a C₁-linker.

Another interesting group of compounds are those compounds of formula(I) wherein L represents a C₁-linker substituted with a C₁₋₄alkyl,C₁₋₄alkyloxyC₁₋₄alkyl-, hydroxyC₁₋₄alkyl- or phenylC₁₋₄alkyl- whereinsaid C₁₋₄alkyl, C₁₋₄alkyloxyC₁₋₄alkyl-, hydroxyC₁₋₄alkyl- orphenylC₁₋₄alkyl- is in the S-configuration

In a preferred embodiment the compounds of formula (I) are selected fromthe group consisting of;

-   3-[(2,6-Dichlorophenyl)methyl]-1-(1-phenylpropyl)-2-pyrrolidinone;-   3-[(2,6-Difluorophenyl)methyl]-1-(1-phenylethyl)-2-pyrrolidinone;-   3-[(2,6-Dimethylphenyl)methyl]-1-(1-phenylethyl)-2-piperidinone;-   3-[(6-Chloro-1,3-benzodioxol-5-yl)methyl]-1-(1-phenylethyl)-2-pyrrolidinone;-   3-[1-(2-Methylphenyl)ethyl]-1-(1-phenylethyl)-2-pyrrolidinone;-   3-[(2-Chloro-3,4-dimethoxyphenyl)methyl]-1-(1-phenylethyl)-2-pyrrolidinone;-   3-[(2,6-Dichlorophenyl)methyl]-1-(2-phenylethyl)-2-pyrrolidinone;-   3-[(2,6-Dimethylphenyl)methyl]-1-(1-phenylethyl)-2-piperidinone, or-   3-[(2-Methylphenyl)methyl]-1-(1-phenylethyl)-2-pyrrolidinone.    the N-oxides, pharmaceutically acceptable addition salts or a    stereochemically isomeric forms thereof.

In a more preferred embodiment the compounds of formula (I) are selectedfrom the group consisting of

-   3-[(2,6-Dichlorophenyl)methyl]-1-(1-phenylpropyl)-2-pyrrolidinone;-   3-[(2,6-Difluorophenyl)methyl]-1-(1-phenylethyl)-2-pyrrolidinone;-   3-[(2,6-Dimethylphenyl)methyl]-1-(1-phenylethyl)-2-piperidinone;-   3-[(6-Chloro-1,3-benzodioxol-5-yl)methyl]-1-(1-phenylethyl)-2-pyrrolidinone;-   3-[1-(2-Methylphenyl)ethyl]-1-(1-phenylethyl)-2-pyrrolidinone;-   3-[(2,6-Dichlorophenyl)methyl]-1-(2-phenylethyl)-2-pyrrolidinone;-   3-[(2-Methylphenyl)methyl]-1-(1-phenylethyl)-2-pyrrolidinone.    the N-oxides, pharmaceutically acceptable addition salts or a    stereochemically isomeric forms thereof

In a further aspect the present invention provides any of theaforementioned group of compounds for use as a medicine. In particularin the treatment or prevention of parthologies associated with excesscortisol formation such as obesity, diabetes, obesity relatedcardiovascular diseases and glaucoma.

The 1,3-pyrrolidinine derivatives of the present invention are generallyprepared by alkylation of the appropriate lactam (II) with anappropriate alkyl halide (III) in the presence of a base such as forexample (diisopropylamino)lithium (LDA) or sec-butyllithium, optionallyin the present of a co-solvent such as for exampleN,N′,N″-Hexamethylphosphoramide (HMPA) or a salt such as for exampleLiBr (Scheme 1). This reaction is usually performed in an inert solventsuch as for example diisopropylether, tetrahydrofuran or methylenechloride. The reaction temperature and the reaction time may be altereddepending on the starting material or reagents but is usually performedwithin a couple of hours at low temperatures (−50° C.-−90° C.). In somecases the coupling reaction is slow and the mixture has to be kept untilcompletion. In these cases the temperature could be enhanced up to (−10°C.-−30° C.).

The appropriate lactam of formula (II) hereinbefore, is generallyprepared by reacting the known amines of formula (IV) with either4-chlorobutanoyl chloride or 5-chloropentanoyl chloride in the presenceof a base, such as for example sodium hydroxide, potassium hydroxide,sodiumcarbonate or sodium hydrogen carbonate, in an appropriate solventsuch as for example dichloromethane, diisopropylether, tetrahydrofuranor methylene chloride (Scheme 2). The reaction is typically performed intwo steps, wherein, in a first step the 4-chlorobutanoyl chloride or5-chloropentanoyl chloride is added to the amine of formula (IV) underbasic conditions, using for example triethylamine in dichloromethane, toform the amide of formula (V). In the second step, upon addition of astrong base such as sodium hydroxide, an internal nucleophilic additionreaction provides the lactam of formula (II).

The amines of formula (IV) are generally prepared using art knowntechniques, see for instance in; “Introduction to organic chemistry”Streitweiser and Heathcock—Macmillan Publishing Co., Inc.—secondedition—New York—Section 24.6 p 742-753, and comprise synthesis throughindirect alkylation of the appropriate (hetero)aryl 113 halides inparticular by the Gabriel synthesis, through reduction of thecorresponding nitro or nitrille compounds, through reductive aminationusing for example the Eschweiler-Clarke reaction and in particular forethose compounds of formula (I) wherein L represents an optionallysubstituted C₁-alkyl, through the reduction of oximes (VI) which may beprepared from aldehydes or ketones (VII) by reaction with hydroxylamine(scheme 3). In this latter case the oximes are reduced by lithiumaluminium hydride or catalytic hydrogenation using an appropriatecatalysator such as Raney Nickel, said reduction being performed in aninert anhydrous solvent such as ether or tetrahydrofuran (THF).

-   -   Wherein R′ represents a C₁₋₄alkyl, C₁₋₃alkyloxy-C₁₋₄alkyl,        hydroxy-C₁₋₄alkyl, C₁₋₃alkyloxy- or phenyl-C₁₋₄alkyl- and R⁶ is        defined as for the compounds of formula (I).

Further examples for the synthesis of compounds of formula (I) usinganyone of the above mentioned synthesis methods, are provided in theexperimental part hereinafter.

Where necessary or desired, any one or more of the following furthersteps in any order may be performed:

-   (i) removing any remaining protecting group(s);-   (ii) converting a compound of formula (I) or a protected form    thereof into a further compound of formula (I) or a protected form    thereof;-   (iii) converting a compound of formula (I) or a protected form    thereof into a N-oxide, a salt, a quaternary amine or a solvate of a    compound of formula (I) or a protected form thereof;-   (iv) converting a N-oxide, a salt, a quaternary amine or a solvate    of a compound of formula (I) or a protected form thereof into a    compound of formula (I) or a protected form thereof;-   (v) converting a N-oxide, a salt, a quaternary amine or a solvate of    a compound of formula (I) or a protected form thereof into another    N-oxide, a pharmaceutically acceptable addition salt a quaternary    amine or a solvate of a compound of formula (I) or a protected form    thereof;-   (vi) where the compound of formula (I) is obtained as a mixture    of (R) and (S) enantiomers resolving the mixture to obtain the    desired enantiomer;

It will be appreciated by those skilled in the art that in the processesdescribed above the functional groups of intermediate compounds may needto be blocked by protecting groups.

Functional groups which it is desirable to protect include hydroxy,amino and carboxylic acid. Suitable protecting groups for hydroxyinclude trialkylsilyl groups (e.g. tert-butyldimethylsilyl,tert-butyldiphenylsilyl or trimethylsilyl), benzyl andtetrahydropyranyl. Suitable protecting groups for amino includetert-butyloxycarbonyl or benzyloxycarbonyl. Suitable protecting groupsfor carboxylic acid include C₍₁₋₆₎alkyl or benzyl esters.

The protection and deprotection of functional groups may take placebefore or after a reaction step.

The use of protecting groups is fully described in ‘Protective Groups inOrganic Synthesis’ 2^(nd) edition, T W Greene & P G M Wutz, WileyInterscience (1991).

Additionally, the N-atoms in compounds of formula (I) can be methylatedby art-known methods using CH₃—I in a suitable solvent such as, forexample 2-propanone, tetrahydrofuran or dimethylformamide.

The compounds of formula (I), can also be converted into each otherfollowing art-known procedures of functional group transformation ofwhich some examples are mentioned hereinabove.

The compounds of formula (I), may also be converted to the correspondingN-oxide forms following art-known procedures for converting a trivalentnitrogen into its N-oxide form. Said N-oxidation reaction may generallybe carried out by reacting the starting material of formula (I) with3-phenyl-2-(phenylsulfonyl)oxaziridine or with an appropriate organic orinorganic peroxide. Appropriate inorganic peroxides comprise, forexample, hydrogen peroxide, alkali metal or earth alkaline metalperoxides, e.g. sodium peroxide, potassium peroxide; appropriate organicperoxides may comprise peroxy acids such as, for example,benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid,e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g.peroxoacetic acid, alkylhydroperoxides, e.g. t-butyl hydroperoxide.Suitable solvents are, for example, water, lower alkanols, e.g. ethanoland the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone,halogenated hydrocarbons, e.g. dichloromethane, and mixtures of suchsolvents.

Pure stereochemically isomeric forms of the compounds of formula (I),may be obtained by the application of art-known procedures.Diastereomers may be separated by physical methods such as selectivecrystallization and chromatographic techniques, e.g. counter-currentdistribution, liquid chromatography and the like.

Some of the compounds of formula (I), and some of the intermediates inthe present invention may contain an asymmetric carbon atom. Purestereochemically isomeric forms of said compounds and said intermediatescan be obtained by the application of art-known procedures. For example,diastereoisomers can be separated by physical methods such as selectivecrystallization or chromatographic techniques, e.g. counter currentdistribution, liquid chromatography and the like methods. Enantiomerscan be obtained from racemic mixtures by first converting said racemicmixtures with suitable resolving agents such as, for example, chiralacids, to mixtures of diastereomeric salts or compounds; then physicallyseparating said mixtures of diastereomeric salts or compounds by, forexample, selective crystallization or chromatographic techniques, e.g.liquid chromatography and the like methods; and finally converting saidseparated diastereomeric salts or compounds into the correspondingenantiomers. Pure stereochemically isomeric forms may also be obtainedfrom the pure stereochemically isomeric forms of the appropriateintermediates and starting materials, provided that the interveningreactions occur stereospecifically.

An alternative manner of separating the enantiomeric forms of thecompounds of formula (I) and intermediates involves liquidchromatography, in particular liquid chromatography using a chiralstationary phase.

Some of the intermediates and starting materials as used in the reactionprocedures mentioned hereinabove are known compounds and may becommercially available or may be prepared according to art-knownprocedures.

The compounds of the present invention are useful because they possesspharmacological properties. They can therefore be used as medicines, inparticular to treat pathologies associated with excess cortisolformation such as for example, obesity, diabetes, obesity relatedcardiovascular diseases, and glaucoma.

As described in the experimental part hereinafter, the inhibitory effectof the present compounds on the 11β-HSD1-reductase activity (conversionof cortison into cortisol) has been demonstrated in vitro, in anenzymatic assay using the recombinant 11b-HSD1 enzyme, by measuring theconversion of cortison into cortisol using HPLC purification andquantification methods. 11β-HSD1-reductase inhibition was alsodemonstrated in vitro, in a cell based assay comprising contacting thecells, expressing 11β-HSD1 with the compounds to be tested and assessingthe effect of said compounds on the formation of cortisol in thecellular medium of these cells. The cells preferably used in an assay ofthe present invention are selected from the group consisting of mousefibroblast 3T3-L1 cells, HepG2 cells, pig kidney cell, in particularLCC-PK1 cells and rat hepatocytes.

Accordingly, the present invention provides the compounds of formula (I)and their pharmaceutically acceptable N-oxides, addition salts,quaternary amines and stereochemically isomeric forms for use intherapy. More particular in the treatment or prevention of parthologiesassociated with excess cortisol formation such as obesity, diabetes,obesity related cardiovascular diseases and glaucoma. The compounds offormula (I) and their pharmaceutically acceptable N-oxides, additionsalts, quaternary amines and the stereochemically isomeric forms mayhereinafter be referred to as compounds according to the invention.

In view of the utility of the compounds according to the invention,there is provided a method for the treatment of an animal, for example,a mammal including humans, suffering from a pathology associated withexcess cortisol formation, which comprises administering an effectiveamount of a compound according to the present invention. Said methodcomprising the systemic or topical administration of an effective amountof a compound according to the invention, to warm-blooded animals,including humans.

It is thus an object of the present invention to provide a compoundaccording to the present invention for use as a medicine. In particularto use the compound according to the present invention in themanufacture of a medicament for treating pathologies associated withexcess cortisol formation such as for example, obesity, diabetes,obesity related cardiovascular diseases, and glaucoma.

The amount of a compound according to the present invention, alsoreferred to here as the active ingredient, which is required to achievea therapeutical effect will be, of course, vary with the particularcompound, the route of administration, the age and condition of therecipient, and the particular disorder or disease being treated. Asuitable daily dose would be from 0.001 mg/kg to 500 mg/kg body weight,in particular from 0.005 mg/kg to 100 mg/kg body weight. A method oftreatment may also include administering the active ingredient on aregimen of between one and four intakes per day.

While it is possible for the active ingredient to be administered alone,it is preferable to present it as a pharmaceutical composition.Accordingly, the present invention further provides a pharmaceuticalcomposition comprising a compound according to the present invention,together with a pharmaceutically acceptable carrier or diluent. Thecarrier or diluent must be “acceptable” in the sense of being compatiblewith the other ingredients of the composition and not deleterious to therecipients thereof.

The pharmaceutical compositions of this invention may be prepared by anymethods well known in the art of pharmacy, for example, using methodssuch as those described in Gennaro et al. Remington's PharmaceuticalSciences (18^(th) ed., Mack Publishing Company, 1990, see especiallyPart 8: Pharmaceutical preparations and their Manufacture). Atherapeutically effective amount of the particular compound, in baseform or addition salt form, as the active ingredient is combined inintimate admixture with a pharmaceutically acceptable carrier, which maytake a wide variety of forms depending on the form of preparationdesired for administration. These pharmaceutical compositions aredesirably in unitary dosage form suitable, preferably, for systemicadministration such as oral, percutaneous, or parenteral administration;or topical administration such as via inhalation, a nose spray, eyedrops or via a cream, gel, shampoo or the like. For example, inpreparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed, such as, for example, water,glycols, oils, alcohols and the like in the case of oral liquidpreparations such as suspensions, syrups, elixirs and solutions: orsolid carriers such as starches, sugars, kaolin, lubricants, binders,disintegrating agents and the like in the case of powders, pills,capsules and tablets. Because of their ease in administration, tabletsand capsules represent the most advantageous oral dosage unit form, inwhich case solid pharmaceutical carriers are obviously employed. Forparenteral compositions, the carrier will usually comprise sterilewater, at least in large part, though other ingredients, for example, toaid solubility, may be included. Injectable solutions, for example, maybe prepared in which the carrier comprises saline solution, glucosesolution or a mixture of saline and glucose solution. Injectablesuspensions may also be prepared in which case appropriate liquidcarriers, suspending agents and the like may be employed. In thecompositions suitable for percutaneous administration, the carrieroptionally comprises a penetration enhancing agent and/or a suitablewettable agent, optionally combined with suitable additives of anynature in minor proportions, which additives do not cause anysignificant deleterious effects on the skin. Said additives mayfacilitate the administration to the skin and/or may be helpful forpreparing the desired compositions. These compositions may beadministered in various ways, e.g., as a transdermal patch, as a spot-onor as an ointment. As appropriate compositions for topical applicationthere may be cited all compositions usually employed for topicallyadministering drugs e.g. creams, gellies, dressings, shampoos,tinctures, pastes, ointments, salves, powders and the like. Applicationof said compositions may be by aerosol, e.g. with a propellant such asnitrogen, carbon dioxide, a freon, or without a propellant such as apump spray, drops, lotions, or a semisolid such as a thickenedcomposition which can be applied by a swab. In particular, semisolidcompositions such as salves, creams, gellies, ointments and the likewill conveniently be used.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable solutions or suspensions, teaspoonfuls, tablespoonfuls andthe like, and segregated multiples thereof.

In order to enhance the solubility and/or the stability of the compoundsof formula (I) in pharmaceutical compositions, it can be advantageous toemploy α-, β- or γ-cyclo-dextrins or their derivatives. Also co-solventssuch as alcohols may improve the solubility and/or the stability of thecompounds of formula (I) in pharmaceutical compositions. In thepreparation of aqueous compositions, addition salts of the subjectcompounds are obviously more suitable due to their increased watersolubility.

EXPERIMENTAL PART

Hereinafter, the term ‘RT’ means room temperature, ‘THF’ meanstetrahydrofuran, ‘Et₂O’ means diethylether, ‘DCM means dichloromethane,‘LDA’ means (diisopropylamino)lithium.

A. Preparation of the Intermediates Example A1 Preparation ofIntermediate 1

To a stirred solution of alfa-(S)-methyl benzylamine (0.05 mol) andtriethylamine (Et₃N) (0.055 mol) in DCM (200 ml) was added dropwise asolution of 4-chlorobutanoyl chloride (0.055 mol) in DCM (100 ml) at−10° C. After the addition, the reaction mixture was stirred at roomtemperature until total conversion (TLC monitoring). The reactionmixture was washed twice with 1N HCl. To the organic phase were added100 ml of 50% sodium hydroxide solution together with benzyl-triethylammonium chloride (0.05 mol). The mixture was stirred vigorously at roomtemperature overnight. The thus obtained reaction mixture was washedwith 1N HCl, 5% NaHCO₃ solution, water and brine. The organic phase wasseparated, dried over magnesium sulphate and concentrated to give 9.5 gof intermediate 1 as colourless oil.

Alternatively intermediate 1 is prepared according to the followingreaction scheme;

To a stirred solution of 7 ml Et₃N in 300 ml CH₂Cl₂ was introduceddropwise within 0.5 hour a solution of 6.00 g (0.0495 mol) 1 in 100 mlCH₂Cl₂. The mixture was stirred at RT until no starting amine 1 wasmonitored by TLC (eluted with Et₂O; the formation of the intermediate 2could be monitored R_(f)=0.5). The mixture was washed with 2N HCl (toremove the Et₃N still present). To the reaction mixture were introducedTEBA (benzyltriethylammonium chloride) 1.13 g (0.00495 mol) and NaOH(aq.) (50 g in 60 ml H₂O). The mixture was stirred overnight, organiclayer was separated and acidified with 2N HCl. It was washed with NaHCO₃(5%), H₂O and dried (NaSO₄). After evaporation of the solvent 10.10 gcrude product were isolated. It was chromatographed (column h=260 mm,Ø=46 mm, 195 g silicagel 230-400 mesh, eluent Et₂O) to give 1.43 g ofintermediate 3 and 7.28 g of 4 (78%).

NMR data for 4: CDCl3, 1.52 (d, 3H, CH₃); 1.93 (m, 2H, CH₂); 2.42 (m,2H, CH₂); 2.99 and 3.31 (2×m, H^(A) and H^(B), NCH₂); 5.50 (quart, 1H,NCH); 7.32-7.48 (m, 5H-aromatic).

Example A2 a) Preparation of Intermediate 5

A mixture of α-methyl-α-(2-oxoethyl)-benzeneacetonitrile (0.0086 mol)and (S)-α-methyl-benzenemethanamine (0.009 mol) in methanol (50 ml) washydrogenated overnight with palladium on activated carbon (0.5 g) as acatalyst in the presence of a thiophene solution (1 ml). After uptake ofhydrogen (1 equiv.), the catalyst was filtered off and the filtrate wasevaporated, yielding 2.2 g of intermediate 5.

b) Preparation of Intermediate 6

A mixture of intermediate 5 (0.007 mol) in sulfuric acid (25 ml) wasstirred at room temperature over the weekend. The reaction mixture waspoured out into ice, then to neutralised with a NaOH solution. (50%) andextracted with dichloromethane. The organic layer was separated, washed,dried, filtered and the solvent was evaporated, yielding 1.8 g (85.7%)of intermediate 6.

c) Preparation of Intermediate 7

A mixture of intermediate 6 (0.0057 mol) in hydrobromic acid (48%) (50ml) was stirred and refluxed for 1 hour, then for 3 hours. The reactionmixture was cooled and filtered, yielding 1.4 g of intermediate (7).

B. Preparation of the Compounds Example B1 Preparation of Compound 1

And of Compound 2

To a stirred solution of 0.60 g (3.17 mmol) of intermediate 1 in 15 mlTHF, cooled to −80° C., were added 1.2 equivalents of LDA (2M solutionin THF/heptane/ethylbenzene) and the mixture was stirred for 30-45minutes at −80° C. The corresponding benzylhalogenide, i.e.1-methyl-2-chloromethylbenzene (1.05 equivalents) was added at −80° C.and the reaction mixture was stirred 1 hour at this temperature and forone additional hour at −60° C. The reaction was monitored by TLC andkept at −60° C. until completion. The thus obtained reaction mixture washydrolized with 2N HCl, extracted with Et₂O, washed with 5% aq. NaHCO₃and dried over Na₂SO₄. The purification of the diastereoisomers occurredby column chromatography on silica gel (230-400 mesh) with petroleumether/Et₂O (from 2:1 to 4:1 depending on the corresponding compound),yielding compounds 1 and 2.

Example B2 Preparation of Compound 13

And of Compound 14

In a flame dried Schlenk-flask 0.80 g (4.23 mmol) of intermediate 1 weredissolved in 5 ml THF and cooled to −80° C. LDA (1.3 equivalent, 2.7 ml,ca. 2M commercial solution in THF/heptane/ethylbenzene) was introducedvia syringe and the mixture was stirred for 30 minutes at −80° C.2,6-Dichlorobenzyl bromide (1.42 g, 5.92 mmol) was introduced in solidform and the reaction mixture was stirred for 30 minutes at −80° C.until completion of the reaction (proved by TLC). The mixture wasquenched with 2N HCl, then extracted with Et₂O and the organic layerwashed with NaHCO₃ (5% aq.), H₂O, and dried with Na₂SO₄. Afterevaporation of the solvent 1.81 g of the crude product were isolated. Itwas chromatographed (column h=580 mm, 0=32 mm, 180 g silicagel 230-400mesh, eluent petroleum ether/Et₂O=5:1) to give 0.61 g Compound 14 ( )(colourless crystals m.p. 75-76° C.) and 0.75 g Compound 13 ( )(colourless crystals m.p. 98-99° C.), corresponds to 93% total yield.

Table 1 lists the compounds that were prepared according to the aboveExamples.

TABLE 1

Co. No. 3

Co. No. 4

Co. No. 5

Co. No. 6

Co. No. 7

Co. No. 8

Co. No. 9

Co. No. 10

Co. No. 11

Co. No. 12

Co. No. 13

Co. No. 14

Co. No. 15

Co. No. 16

Co. No. 17

Co. No. 18

Co. No. 19

Co. No. 20

Co. No. 21

Co. No. 22

Co. No. 23

Co. No. 24

Co. No. 25

Co. No. 26

Co. No. 27

Co. No. 28

Co. No. 29

Co. No. 30

Co. No. 31

Co. No. 32

Co. No. 33

Co. No. 34

Co. No. 35

Co. No. 36

Co. No. 37

Co. No. 38

Co. No. 39

Co. No. 40

Co. No. 41

Co. No. 42

Co. No. 43

Co. No. 44

Co. No. 45

Co. No. 46

Co. No. 47

Co. No. 48

Co. No. 49

Co. No. 50

Co. No. 51

Co. No. 52

Co. No. 53

Co. No. 54

Co. No. 55

Co. No. 56

Co. No. 57

Co. No. 58

Co. No. 59

Co. No. 60

Co. No. 61

Co. No. 62

Co. No. 63

Co. No. 64

Co. No. 65

Co. No. 66

Co. No. 67

Co. No. 68

Co. No. 69

Co. No. 70

Co. No. 71

Co. No. 72

Co. No. 73

Co. No. 74

Co. No. 75

Co. No. 76

Co. No. 77

Co. No. 78

Co. No. 79

Co. No. 80

Co. No. 81

Co. No. 82

Co. No. 83

Co. No. 84

Co. No. 85

Co. No. 86

Co. No. 87

Co. No. 88

Co. No. 89

Co. No. 90

Co. No. 91

Co. No. 92

Co. No. 93

Co. No. 94

Co. No. 95

Co. No. 96

Co. No. 97

Co. No. 98

Co. No. 99

Co. No. 100

Co. No. 101

Co. No. 102

Co. No. 103

Co. No. 104

Co. No. 105

Co. No. 106

Co. No. 107

Co. No. 108

Co. No. 109

Co. No. 110

Co. No. 111

Co. No. 112

Co. No. 113

Co. No. 114

Co. No. 115

Co. No. 116

Co. No. 117

Co. No. 118

Co. No. 119

Co. No. 120

Co. No. 121

Co. No. 122

Co. No. 123

Co. No. 124

Co. No. 125

Co. No. 126

Co. No. 127

Co. No. 128

Co. No. 129

Co. No. 130

Co. No. 131

Co. No. 132

Co. No. 133

Co. No. 134

Co. No. 135

Co. No. 136

Co. No. 137

Co. No. 138

Co. No. 139

Co. No. 140

Co. No. 141

Co. No. 142

Co. No. 143

Co. No. 144

Co. No. 145

Co. No. 146

Co. No. 147

Co. No. 148

Co. No. 149

Co. No. 150

Co. No. 151

Co. No. 152

Co. No. 153

Co. No. 154

Co. No. 155

Co. No. 156

Co. No. 157

Co. No. 158

Co. No. 159

Co. No. 160

Co. No. 161

Co. No. 162

Co. No. 163

Co. No. 164

Co. No. 165

Example B3 Preparation of Compound 166

A mixture of intermediate 7 (0.00033 mol) in thionyl chloride (2 ml) wasstirred and refluxed for 2 hours, then stirred and refluxed over theweekend at room temperature. The solvent was evaporated and the residuewas dissolved in dichloromethane, washed with water and filtered throughExtrelut, then evaporated. The residue was purified by flash columnchromatography on Triconex flash tubes (eluent: CH₂Cl₂/EtOAc 95/5). Theproduct fractions were collected and the solvent was evaporated,yielding 0.0588 g to (62.5%) of compound 166.

In a Similar Way was Prepared Compound 167

Co. melting No. NMR data point (° C.) 1 CDCl₃; 1.52 (d, CH₃); 1.45-1.67(m, H^(A)-CH₂); 1.91-2.09 (m, H^(B)- CH₂); 2.33 (s, CH₃); 2.47-2.60 (m,H^(A)-CH₂); 2.68-2.83 (m, CH); 2.83-2.97 (dt, H^(A)-CH₂); 3.10-3.25 (m,H^(B)-CH₂); 3.32-3.43 (dd, H^(B)-CH₂); 5.52 (q, CH); 7.03-7.18 (m,4H-aromatic); 7.20-7.39 (m, 5H-aromatic) 2 CDCl₃; 1.41 (d, CH₃);1.46-1.62 (m, H^(A)-CH₂); 1.72-1.89 (m, H^(B)- CH₂); 2.23 (s, CH₃);2.40-2.62 (m, CH, H^(A)-CH₂); 2.62-2.75 (m, H^(A)-CH₂); 3.00-3.12 (dt,H^(B)-CH₂); 3.19-3.30 (dd, H^(B)-CH₂); 5.43 (q, CH); 6.93-7.07 (m,4H-aromatic); 7.08-7.25 (m, 5H-aromatic) 3 CDCl₃; 1.38 (d, CH₃);1.51-1.69 (m, H^(A)-CH₂); 1.79-1.95 (m, H^(B)- CH₂); 2.25 (s, CH₃);2.53-2.78 (m, CH, 2x H^(A)-CH₂); 2.90-3.03 (dt, H^(B)-CH₂); 3.04-3.19(m, H^(B)-CH₂); 5.44 (q, CH); 7.03 (s, 4H- aromatic); 7.12-7.30 (m,5H-aromatic) 4 CDCl₃; 1.53 (d, CH₃); 1.51-1.70 (m, H^(A)-CH₂); 1.92-2.08(m, H^(B)- CH₂); 2.33 (s, CH₃); 2.61-2.88 (m, CH, 2x H^(A)-CH₂);3.11-3.27 (m, 2x H^(B)-CH₂); 5.52 (q, CH); 7.09 (s, 4H-aromatic);7.18-7.38 (m, 5H-aromatic) 5 CDCl₃; 1.45 (d, CH₃); 1.59-1.80 (m,H^(A)-CH₂); 1.82-2.02 (m, H^(B)- CH₂); 2.62-2.88 (m, CH, 2x H^(A)-CH₂);2.91-3.10 (m, H^(B)-CH₂); 3.13-3.31 (m, H^(B)-CH₂); 5.52 (q, CH);7.09-7.42 (m, 10H-aromatic) 6 CDCl₃; 1.50 (d, CH₃); 1.48-1.67 (m,H^(A)-CH₂); 1.88-2.04 (m, H^(B)- CH₂); 2.60-2.87 (m, CH, 2x H^(A)-CH₂);3.08-3.28 (m, 2x H^(B)-CH₂); 5.49 (q, CH); 7.10-7.36 (m, 10H-aromatic) 7CDCl₃; 1.50 (d, CH₃); 1.50-1.65 (m, H^(A)-CH₂); 1.82-1.98 (m, H^(B)-CH₂); 2.50-2.63 (m, H^(A)-CH₂); 2.75-2.92 (m, CH, H^(A)-CH₂); 3.07-3.20(m, H^(B)-CH₂); 3.30-3.42 (dd, H^(B)-CH₂); 3.79 (s, CH₃); 5.51 (q, CH);6.78-6.90 (m, 2H-aromatic); 7.10-7.19 (m, 2H-aromatic); 7.19-7.37 (m,5H-aromatic) 8 CDCl₃; 1.42 (d, CH₃); 1.51-1.70 (m, H^(A)-CH₂); 1.70-1.86(m, H^(B)- CH₂); 2.47-2.61 (m, H^(A)-CH₂); 2.63-2.80 (m, CH, H^(A)-CH₂);2.98-3.12 (dt, H^(B)-CH₂); 3.20-3.32 (dd, H^(B)-CH₂); 3.73 (s, CH₃);5.45 (q, CH); 6.71-6.85 (m, 2H-aromatic); 7.03-7.30 (m, 7H-aromatic) 9CDCl₃; 1.51 (d, CH₃); 1.58-1.81 (m, H^(A)-CH₂); 1.83-2.00 (m, H^(B)-CH₂); 2.71-2.90 (m, CH, 2x H^(A)-CH₂); 3.10-3.22 (dt, H^(B)-CH₂);3.33-3.49 (m, H^(B)-CH₂); 5.53 (q, CH); 7.09-7.38 (m, 9H-aromatic) 10CDCl₃; 1.51 (d, CH₃); 1.52-1.68 (m, H^(A)-CH₂); 1.90-2.07 (m, H^(B)-CH₂); 2.70-2.97 (m, CH, 2x H^(A)-CH₂); 3.12-3.25 (m, H^(B)-CH₂);3.37-3.49 (dd, H^(B)-CH₂); 5.50 (q, CH); 7.09-7.39 (m, 9H-aromatic) 11CDCl₃; 1.46 (d, CH₃); 1.50-1.73 (m, H^(A)-CH₂); 1.78-1.97 (m, H^(B)-CH₂); 2.67-2.86 (m, CH, 2x H^(A)-CH₂); 3.03-3.18 (dt, H^(B)-CH₂);3.30-3.48 (m, H^(B)-CH₂); 5.46 (q, CH); 7.00-7.32 (m, 8H-aromatic) 12CDCl₃; 1.51 (d, CH₃); 1.50-1.67 (m, H^(A)-CH₂); 1.90-2.07 (m, H^(B)-CH₂); 2.75-2.96 (m, CH, 2x H^(A)-CH₂); 3.10-3.25 (m, H^(B)-CH₂);3.40-3.51 (dd, H^(B)-CH₂); 5.50 (q, CH); 7.02-7.37 (m, 8H-aromatic) 13CDCl₃; 1.56 (d, CH₃); 1.78-1.92 (m, CH₂); 2.76-2.88 (m, H^(A)-CH₂);2.88-3.00 (m, CH); 3.01-3.16 (m, H^(A)-CH₂); 3.28-3.38 (m, H^(B)- CH₂);3.43-3.57 (dd, H^(B)-CH₂); 5.53 (q, CH); 7.01-7.12 (m, 1H- aromatic);7.18-7.38 (m, 7H-aromatic) 14 CDCl₃; 1.52 (d, CH₃); 1.68-1.88 (m,H^(A)-CH₂); 1.83-1.99 (m, H^(B)- CH₂); 2.88-3.08 (m, CH, 2x H^(A)-CH₂);3.08-3.24 (m, H^(B)-CH₂); 3.48-3.60 (dd, H^(B)-CH₂); 5.51 (q, CH);7.02-7.13 (m, 1H-aromatic); 7.22-7.42 (m, 7H-aromatic) 15 CDCl₃; 1.46(d, CH₃); 1.60-1.77 (m, H^(A)-CH₂); 1.87-2.02 (m, H^(B)- CH₂); 2.32 (s,CH₃); 2.61-2.83 (m, CH, 2x H^(A)-CH₂); 2.97-3.09 (dt, H^(B)-CH₂);3.11-3.27 (m, H^(B)-CH₂); 5.52 (q, CH); 6.95-7.07 (m, 3H- aromatic);7.11-7.37 (m, 6H-aromatic) 16 CDCl₃; 1.51 (d, CH₃); 1.51-1.63 (m,H^(A)-CH₂); 1.90-2.07 (m, H^(B)- CH₂); 2.31 (s, CH₃); 2.58-2.70 (m,H^(A)-CH₂); 2.70-2.89 (m, CH, H^(A)-CH₂); 3.09-3.28 (m, 2x H^(B)-CH₂);5.50 (q, CH); 6.93-7.06 (m, 3H-aromatic); 7.09-7.37 (m, 6H-aromatic) 17CDCl₃; 1.46 (d, CH₃); 1.57-1.73 (m, H^(A)-CH₂); 1.88-2.02 (m, H^(B)-CH₂); 2.63-2.83 (m, CH, 2x H^(A)-CH₂); 2.97-3.09 (dt, H^(B)-CH₂);3.10-3.25 (m, H^(B)-CH₂); 5.51 (q, CH); 7.04-7.37 (m, 9H-aromatic) 18CDCl₃; 1.50 (d, CH₃); 1.46-1.62 (m, H^(A)-CH₂); 1.90-2.07 (m, H^(B)-CH₂); 2.62-2.87 (m, CH, 2x H^(A)-CH₂); 3.09-3.23 (m, 2x H^(B)-CH₂); 5.49(q, CH); 7.00-7.36 (m, 9H-aromatic) 19 CDCl₃; 1.47 (d, CH₃); 1.60-1.78(m, H^(A)-CH₂); 1.87-2.03 (m, H^(B)- CH₂); 2.61-2.87 (m, CH, 2xH^(A)-CH₂); 3.00-3.13 (dt, H^(B)-CH₂); 3.16-3.27 (m, H^(B)-CH₂); 3.79(s, CH₃); 5.51 (q, CH); 7.71-7.85 (m, 3H-aromatic); 7.16-7.85 (m,6H-aromatic) 20 CDCl₃; 1.51 (d, CH₃); 1.51-1.69 (m, H^(A)-CH₂);1.92-2.07 (m, H^(B)- CH₂); 2.58-2.90 (m, CH, 2x H^(A)-CH₂); 3.10-3.28(m, 2x H^(B)-CH₂); 3.77 (s, CH₃); 5.50 (q, CH); 6.70-6.80 (m,3H-aromatic); 7.11-7.37 (m, 6H-aromatic) 21 CDCl₃; 1.44 (d, CH₃);1.60-1.77 (m, H^(A)-CH₂); 1.87-2.01 (m, H^(B)- CH₂); 2.61-2.82 (m, CH,2x H^(A)-CH₂); 2.96-3.08 (dt, H^(B)-CH₂); 3.08-3.19 (m, H^(B)-CH₂); 3.77(s, CH₃); 5.50 (q, CH); 6.78-6.86 (m, 2H-aromatic); 7.08-7.18 (m,2H-aromatic); 7.20-7.37 (m, 5H- aromatic) 22 CDCl₃; 1.49 (d, CH₃);1.50-1.68 (m, H^(A)-CH₂); 1.89-2.05 (m, H^(B)- CH₂); 2.60-2.82 (m, CH,2x H^(A)-CH₂); 3.05-3.21 (m, 2x H^(B)-CH₂); 3.76 (s, CH₃); 5.48 (q, CH);6.71-6.80 (m, 2H-aromatic); 7.01-7.13 (m, 2H-aromatic); 7.14-7.33 (m,5H-aromatic) 23 CDCl₃; 1.60-1.78 (m, H^(A)-CH₂); 1.93-2.09 (m,H^(B)-CH₂); 2.68-2.88 (m, CH, CH₂); 2.90-3.21 (m, 2x H^(A)-CH₂,H^(B)-CH₂); 3.27-3.38 (dd, H^(B)-CH₂); 3.42-3.65 (m, CH₂); 7.12-7.67 (m,9H-aromatic) 24 CDCl₃; 1.47-1.72 (m, H^(A)-CH₂); 1.89-2.04 (m,H^(B)-CH₂); 2.50-2.75 (m, CH, H^(A)-CH₂); 2.76-2.88 (t, CH₂); 2.93-3.12(m, CH₂); 3.12-3.21 (dd, H^(B)-CH₂); 3.40-3.63 (m, CH₂); 3.79 (s, CH₃);6.71-6.80 (m, 3H-aromatic); 7.12-7.33 (m, 6H-aromatic) 25 CDCl₃;1.61-1.79 (m, H^(A)-CH₂); 1.93-2.08 (m, H^(B)-CH₂); 2.32 (s, CH₃);2.62-2.84 (m, CH, H^(A)-CH₂); 2.96-3.25 (m, H^(A)-CH₂, 2x H^(B)- CH₂);4.44 (dd, CH₂); 7.05-7.34 (m, 9H-aromatic) 26 CDCl₃; 1.45 (d, CH₃);1.58-1.73 (m, H^(A)-CH₂); 1.81-1.99 (m, H^(B)- CH₂); 2.31 (s, CH₃);2.61-2.82 (m, CH, 2x H^(A)-CH₂); 2.75-3.08 (dt, H^(B)-CH₂); 3.09-3.23(m, H^(B)-CH₂); 5.52 (q, CH); 7.02-7.14 (m, 4H- aromatic); 7.18-7.37 (m,5H-aromatic) 27 CDCl₃; 1.42 (d, CH₃); 1.40-1.60 (m, H^(A)-CH₂);1.81-1.99 (m, H^(B)- CH₂); 2.23 (s, CH₃); 2.50-2.78 (m, CH, 2xH^(A)-CH₂); 3.00-3.18 (m, 2x H^(B)-CH₂); 5.41 (q, CH); 6.92-7.07 (m,4H-aromatic); 7.10-7.32 (m, 5H-aromatic) 28 CDCl₃; 1.53-1.71 (m,H^(A)-CH₂); 1.89-2.05 (m, H^(B)-CH₂); 2.23 (s, CH₃); 2.41-2.55 (m,H^(A)-CH₂); 2.59-2.75 (m, CH); 2.80-2.90 (t, CH₂); 3.03-3.20 (m, CH₂);3.23-3.35 (dd, H^(B)-CH₂); 3.44-3.68 (m, CH2); 7.07-7.34 (m,9H-aromatic) 29 CDCl₃; 1.57-1.73 (m, H^(A)-CH₂); 1.89-2.04 (m,H^(B)-CH₂); 2.32 (s, CH₃); 2.50-2.75 (m, CH, H^(A)-CH₂); 2.76-2.88 (t,CH₂); 2.91-3.21 (m, CH₂, H^(B)-CH₂); 3.41-3.65 (m, CH₂); 6.94-7.08 (m,3H- aromatic); 7.12-7.33 (m, 6H-aromatic) 30 CDCl₃; 1.60-1.76 (m,H^(A)-CH₂); 1.88-2.01 (m, H^(B)-CH₂); 2.68-2.90 (m, CH, CH₂, H^(A)-CH₂);3.00-3.19 (m, CH₂); 3.27-3.42 (m, H^(B)- CH₂); 3.43-3.67 (m, CH2);7.10-7.37 (m, 9H-aromatic) 31 CDCl₃; 1.53-1.72 (m, H^(A)-CH₂); 1.88-2.03(m, H^(B)-CH₂); 2.69-2.90 (m, CH, CH₂, H^(A)-CH₂); 3.01-3.20 (m, CH₂);3.31-3.46 (m, H^(B)- CH₂); 3.46-3.67 (m, CH2); 7.07-7.38 (m,8H-aromatic) 32 CDCl₃; 1.72-1.97 (m, CH₂); 2.80-2.91 (t, CH₂); 2.91-3.27(m, CH, 2x H^(A)-CH₂, H^(B)-CH₂); 3.38-3.48 (dd, H^(B)-CH₂); 3.48-3.68(m, CH₂); 7.03-7.35 (m, 8H-aromatic) 33 CDCl₃; 1.56-1.72 (m, H^(A)-CH₂);1.80-1.97 (m, H^(B)-CH₂); 2.47-2.60 (m, H^(A)-CH₂); 2.68-2.80 (m, CH);2.78-2.88 (t, CH₂); 2.99-3.17 (m, CH₂); 3.23-3.35 (dd, H^(B)-CH₂);3.42-3.64 (m, CH₂); 3.81 (s, CH₃); 6.80-6.92 (m, 2H-aromatic); 7.10-7.35(m, 7H-aromatic) 34 CDCl₃; 1.55-1.71 (m, H^(A)-CH₂); 1.77-2.02 (m,H^(B)-CH₂); 2.53-2.76 (m, CH, H^(A)-CH₂); 2.77-2.85 (t, CH₂); 2.90-3.02(dt, H^(A)-CH₂); 3.02-3.14 (m, H^(B)-CH₂); 3.14-3.23 (dd, H^(B)-CH₂);3.40-3.62 (m, CH₂); 7.12-7.33 (m, 10H-aromatic) 35 CDCl₃; 1.56-1.72 (m,H^(A)-CH₂); 1.88-2.02 (m, H^(B)-CH₂); 2.32 (s, CH₃); 2.51-2.73 (m, CH,H^(A)-CH₂); 2.76-2.87 (t, CH₂); 2.90-3.18 (m, CH₂, H^(B)-CH₂); 3.40-3.63(m, CH₂); 7.03-7.33 (m, 9H- aromatic) 36 CDCl₃; 1.38 (d, CH₃); 1.52-1.70(m, H^(A)-CH₂); 1.79-1.96 (m, H^(B)- CH₂); 2.58-2.77 (m, CH, 2xH^(A)-CH₂); 2.90-3.01 (dt, H^(B)-CH₂); 3.07-3.22 (m, H^(B)-CH₂); 5.44(q, CH); 7.08-7.29 (m, 10H-aromatic) 37 CDCl₃; 1.38 (d, CH₃); 1.40-1.58(m, H^(A)-CH₂); 1.77-1.92 (m, H^(B)- CH₂); 2.50-2.75 (m, CH, 2xH^(A)-CH₂); 2.94-3.18 (m, 2x H^(B)-CH₂); 5.39 (q, CH); 7.01-7.28 (m,10H-aromatic) 38 CDCl₃; 1.42 (d, CH₃); 1.52-1.70 (m, H^(A)-CH₂);1.70-1.87 (m, H^(B)- CH₂); 2.47-2.61 (m, H^(A)-CH₂); 2.64-2.80 (m, CH,H^(A)-CH₂); 3.00-3.12 (dt, H^(B)-CH₂); 3.20-3.32 (dd, H^(B)-CH₂); 3.74(s, CH₃); 5.45 (q, CH); 6.72-6.84 (m, 2H-aromatic); 7.03-7.28 (m,7H-aromatic) 39 CDCl₃; 1.44 (d, CH₃); 1.42-1.59 (m, H^(A)-CH₂);1.77-1.91 (m, H^(B)- CH₂); 2.42-2.54 (m, H^(A)-CH₂); 2.70-2.87 (m, CH,H^(A)-CH₂); 3.00-3.13 (m, H^(B)-CH₂); 3.22-3.35 (dd, H^(B)-CH₂); 3.72(s, CH₃); 5.44 (q, CH); 6.71-6.82 (m, 2H-aromatic); 7.02-7.30 (m,7H-aromatic) 40 CDCl₃; 1.38 (d, CH₃); 1.49-1.67 (m, H^(A)-CH₂);1.69-1.87 (m, H^(B)- CH₂); 2.60-2.77 (m, CH, 2x H^(A)-CH₂); 2.97-3.10(dt, H^(B)-CH₂); 3.23-3.38 (m, H^(B)-CH₂); 5.41 (q, CH); 6.95-7.26 (m,9H-aromatic) 41 CDCl₃; 1.43 (d, CH₃); 1.38-1.59 (m, H^(A)-CH₂);1.80-1.99 (m, H^(B)- CH₂); 2.62-2.87 (m, CH, 2x H^(A)-CH₂); 3.01-3.15(m, H^(B)-CH₂); 3.30-3.41 (dd, H^(B)-CH₂); 5.41 (q, CH); 6.95-7.11 (m,2H-aromatic); 7.12-7.29 (m, 7H-aromatic) 42 CDCl₃; 1.48 (d, CH₃);1.54-1.73 (m, H^(A)-CH₂); 1.79-1.97 (m, H^(B)- CH₂); 2.68-2.87 (m, CH,2x H^(A)-CH₂); 3.08-3.22 (m, H^(B)-CH₂); 3.35-3.52 (m, H^(B)-CH₂); 5.49(q, CH); 7.02-7.23 (m, 8H-aromatic) 43 CDCl₃; 1.39 (d, CH₃); 1.32-1.53(m, H^(A)-CH₂); 1.79-1.96 (m, H^(B)- CH₂); 2.60-2.83 (m, CH, 2xH^(A)-CH₂); 3.00-3.13 (m, H^(B)-CH₂); 3.28-3.42 (m, H^(B)-CH₂); 5.38 (q,CH); 6.91-7.27 (m, 8H-aromatic) 44 CDCl₃; 1.45 (d, CH₃); 1.67-1.80 (m,CH₂); 2.64-2.78 (m, H^(A)-CH₂); 2.76-2.89 (m, CH); 2.90-3.03 (m,H^(A)-CH₂); 3.13-3.26 (m, H^(B)- CH₂); 3.37-3.47 (dd, H^(B)-CH₂); 5.43(q, CH); 6.90-7.00 (m, 1H- aromatic); 7.08-7.26 (m, 7H-aromatic) 45CDCl₃; 1.41 (d, CH₃); 1.57-1.73 (m, H^(A)-CH₂); 1.72-1.88 (m, H^(B)-CH₂); 2.78-3.12 (m, CH, 2x H^(A)-CH₂, H^(B)-CH₂); 3.38-3.48 (dd, H^(B)-CH₂); 5.40 (q, CH); 6.90-7.01 (m, 1H-aromatic); 7.10-7.30 (m,7H-aromatic) 46 CDCl₃; 1.39 (d, CH₃); 1.50-1.68 (m, H^(A)-CH₂);1.80-1.97 (m, H^(B)- CH₂); 2.56-2.78 (m, CH, 2x H^(A)-CH₂); 2.89-3.03(dt, H^(B)-CH₂); 3.03-3.18 (m, H^(B)-CH₂); 5.43 (q, CH); 6.97-7.30 (m,9H-aromatic) 47 CDCl₃; 1.39 (d, CH₃); 1.33-1.52 (m, H^(A)-CH₂);1.79-1.95 (m, H^(B)- CH₂); 2.52-2.77 (m, CH, 2x H^(A)-CH₂); 2.97-3.14(m, 2x H^(B)-CH₂); 5.38 (q, CH); 6.89-7.27 (m, 9H-aromatic) 48 CDCl₃;1.61-1.79 (m, H^(A)-CH₂); 1.93-2.08 (m, H^(B)-CH₂); 2.61-2.87 (m, CH,H^(A)-CH₂); 2.98-3.18 (m, CH₂); 3.19-3.29 (dd, H^(B)-CH₂); 3.78 (s,CH₃); 4.45 (q, CH₂); 6.72-6.83 (m, 3H-aromatic); 7.13-7.37 (m,6H-aromatic) 49 CDCl₃; 1.43 (d, CH₃); 1.58-1.77 (m, H^(A)-CH₂);1.85-2.00 (m, H^(B)- CH₂); 2.65-2.82 (m, CH, H^(A)-CH₂); 2.90-3.03 (m,H^(A)-CH₂); 3.05-3.18 (dt, H^(B)-CH₂); 3.28-3.40 (dd, H^(B)-CH₂); 5.43(q, CH); 7.12-7.30 (m, 6H-aromatic); 7.33-7.58 (m, 3H-aromatic) 50CDCl₃; 1.37 (d, CH₃); 1.52-1.68 (m, H^(A)-CH₂); 1.78-1.93 (m, H^(B)-CH₂); 2.55-2.77 (m, CH, 2x H^(A)-CH₂); 2.89-3.12 (m, 2x H^(B)-CH₂); 3.71(s, CH₃); 5.43 (q, CH); 6.75 (m, 2H-aromatic); 7.05 (m, 2H- aromatic);7.12-7.29 (m, 5H-aromatic) 51 CDCl₃; 1.41-1.60 (m, H^(A)-CH₂); 1.77-1.94(m, H^(B)-CH₂); 2.51-2.71 (m, CH, H^(A)-CH₂); 2.81-3.14 (m, CH₂,H^(B)-CH₂); 4.31 (q, CH₂); 6.90-7.23 (m, 9H-aromatic) 52 CDCl₃; 1.46 (d,CH₃); 1.60-1.78 (m, H^(A)-CH₂); 1.88-2.03 (m, H^(B)- CH₂); 2.61-2.85 (m,CH, 2x H^(A)-CH₂); 3.00-3.13 (dt, H^(B)-CH₂); 3.14-3.28 (m, H^(B)-CH₂);3.79 (s, CH₃); 5.51 (q, CH); 6.71-6.83 (m, 3H-aromatic); 7.13-7.38 (m,6H-aromatic) 53 CDCl₃; 1.60-1.79 (m, H^(A)-CH₂); 1.87-2.05 (m,H^(B)-CH₂); 2.60-2.89 (m, CH, H^(A)-CH₂); 2.89-3.17 (m, CH₂, H^(B)-CH₂);4.42 (q, CH₂); 6.60-6.90 (m, 3H-aromatic); 7.01-7.36 (m, 6H-aromatic);8.32 (s, OH) 54 CDCl₃; 1.63-1.85 (m, H^(A)-CH₂); 1.95-2.16 (m,H^(B)-CH₂); 2.75-2.96 (m, CH); 2.98-3.23 (m, CH₂, H^(A)-CH₂); 3.32-3.53(dd, H^(B)-CH₂); 4.46 (s, CH₂); 7.07-7.68 (m, 9H-aromatic) 55 CDCl₃;1.60-1.77 (m, H^(A)-CH₂); 1.95-2.10 (m, H^(B)-CH₂); 2.35 (s, CH₃);2.52-2.68 (m, H^(A)-CH₂); 2.68-2.77 (m, CH); 3.09-3.19 (m, CH₂);3.36-3.44 (dd, H^(B)-CH₂); 4.49 (s, CH₂); 7.08-7.20 (m, 4H- aromatic);7.20-7.38 (m, 5H-aromatic) 56 CDCl₃; 1.60-1.78 (m, H^(A)-CH₂); 1.92-2.07(m, H^(B)-CH₂); 2.32 (m, CH₃); 2.61-2.86 (m, CH, H^(A)-CH₂); 2.97-3.27(m, CH₂, H^(B)-CH₂); 4.44 (q, CH₂); 6.95-7.08 (m, 3H-aromatic);7.11-7.36 (m, 6H- aromatic) 57 CDCl₃; 1.52-1.70 (m, H^(A)-CH₂);1.79-1.97 (m, H^(B)-CH₂); 2.64-2.86 (m, CH, H^(A)-CH₂); 2.95-3.07 (m,H^(A)-CH₂, H^(B)-CH₂); 3.28-3.42 (m, H^(B)-CH₂); 4.37 (s, CH₂);6.99-7.30 (m, 9H-aromatic) 58 CDCl₃; 1.60-1.79 (m, H^(A)-CH₂); 1.93-2.09(m, H^(B)-CH₂); 2.79-2.97 (m, CH, H^(A)-CH₂); 3.07-3.19 (m, CH₂);3.41-3.56 (m, H^(B)-CH₂); 4.47 (s, CH₂); 7.07-7.37 (m, 8H-aromatic) 59CDCl₃; 1.77-1.88 (m, CH₂); 2.81-3.20 (m, 2x CH₂, H^(A)-CH₂); 3.32-3.50(m, H^(B)-CH₂); 4.40 (q, CH₂); 6.95-7.04 (m, 1H-aromatic); 7.12-7.30(7H-aromatic) 60 CDCl₃; 1.62-1.79 (m, H^(A)-CH₂); 1.86-2.02 (m,H^(B)-CH₂); 2.57-2.68 (m, H^(A)-CH₂); 2.79-2.94 (m, CH); 3.03-3.13 (m,CH₂); 3.32-3.42 (dd, H^(B)-CH₂); 3.81 (s, CH₃); 4.46 (s, CH₂); 6.80-6.92(m, 2H- aromatic); 7.11-7.37 (m, 7H-aromatic) 61 CDCl₃; 1.50-1.68 (m,H^(A)-CH₂); 1.82-1.97 (m, H^(B)-CH₂); 2.56-2.77 (m, CH, H^(A)-CH₂);2.83-3.07 (m, CH₂); 3.08-3.22 (m, H^(B)-CH₂); 4.34 (q, CH₂); 7.03-7.26(m, 10H-aromatic) 62 CDCl₃; 1.46 (d, CH₃); 1.52-1.69 (m, H^(A)-CH₂);1.80-1.97 (m, H^(B)- CH₂); 2.28 (s, CH₃); 2.44-2.58 (m, H^(A)-CH₂);2.58-2.69 (m, CH); 2.69-2.82 (m, H^(A)-CH₂); 3.08-3.19 (dt, H^(B)-CH₂);3.24-3.35 (dd, H^(B)-CH₂); 5.47 (q, CH); 7.00-7.12 (m, 4H-aromatic);7.14-7.32 (m, 5H-aromatic) 63 CDCl₃; 1.39 (d, CH₃); 1.52-1.70 (m,H^(A)-CH₂); 1.79-1.95 (m, H^(B)- CH₂); 2.25 (s, CH₃); 2.53-2.77 (m, CH,2x H^(A)-CH₂); 2.90-3.01 (dt, H^(B)-CH₂); 3.05-3.20 (m, H^(B)-CH₂); 5.45(q, CH); 6.89-6.98 (m, 3H- aromatic); 7.05-7.30 (m, 6H-aromatic) 64CDCl₃; 1.44 (d, CH₃); 1.45-1.63 (m, H^(A)-CH₂); 1.91-2.08 (m, H^(B)-CH₂); 2.71-2.87 (m, CH, H^(A)-CH₂); 2.90-3.03 (m, H^(A)-CH₂); 3.04-3.19(m, H^(B)-CH₂); 3.27-3.39 (dd, H^(B)-CH₂); 5.41 (q, CH); 7.10-7.29 (m,6H-aromatic); 7.31-7.46 (m, 2H-aromatic); 7.49-7.57 (m, 1H-aromatic) 65CDCl₃; 1.43 (d, CH₃); 1.47-1.62 (m, H^(A)-CH₂); 1.83-1.98 (m, H^(B)-CH₂); 2.53-2.77 (m, CH, 2x H^(A)-CH₂); 3.01-3.15 (m, 2x H^(B)-CH₂); 3.71(s, CH₃); 5.41 (q, CH); 6.67-6.75 (m, 2H-aromatic); 6.98-7.07 (m,2H-aromatic); 7.09-7.28 (m, 5H-aromatic) 66 CDCl₃; 1.51 (d, CH₃);1.50-1.67 (m, H^(A)-CH₂); 1.91-2.07 (m, H^(B)- CH₂); 2.58-2.90 (m, CH,2x H^(A)-CH₂); 3.10-3.27 (m, 2x H^(B)-CH₂); 3.77 (s, CH₃); 5.49 (q, CH);6.69-6.80 (m, 3H-aromatic); 7.10-7.34 (m, 6H-aromatic) 67 CDCl₃; 1.53(d, CH₃); 1.49-1.68 (m, H^(A)-CH₂); 1.93-2.10 (m, H^(B)- CH₂); 2.35 (s,CH₃); 2.50-2.62 (m, H^(A)-CH₂); 2.70-2.85 (m, CH); 2.87-2.98 (dt,H^(A)-CH₂); 3.13-3.27 (m, H^(B)-CH₂); 3.34-3.45 (dd, H^(B)-CH₂); 5.53(q, CH); 7.05-7.20 (m, 4H-aromatic); 7.22-7.40 (m, 5H-aromatic) 68CDCl₃; 1.44 (d, CH₃); 1.53-1.65 (m, H^(A)-CH₂); 1.83-1.99 (m, H^(B)-CH₂); 2.23 (s, CH₃); 2.49-2.81 (m, CH, 2x H^(A)-CH₂); 3.03-3.20 (m, 2xH^(B)-CH₂); 5.43 (q, CH); 6.88-6.98 (m, 3H-aromatic); 7.02-7.29 (m,6H-aromatic) 69 CDCl₃; 1.37-1.58 (m, H^(A)-CH₂); 1.56 (d, CH₃);1.61-1.77 (m, H^(B)- CH₂); 2.27 (s, CH₃); 2.38 (s, CH₃); 2.73-2.93 (m,CH, H^(A)-CH₂); 3.12-3.27 (dt, H^(B)-CH₂); 4.97 (d, CH); 5.51 (q, CH);6.90-7.04 (m, 2H-aromatic); 7.20-7.38 (m, 6H-aromatic) 70 CDCl₃; 1.45(d, CH₃); 1.53-1.72 (m, H^(A)-CH₂); 1.77-1.91 (m, H^(B)- 58-60 CH₂);2.58-2.79 (m, CH, 2x H^(A)-CH₂); 3.08-3.30 (m, 2x H^(B)-CH₂); 5.45 (q,CH); 6.69-6.82 (m, 2H-aromatic); 7.00-7.29 (m, 6H- aromatic) 71 CDCl₃;1.43 (d, CH₃); 1.57-1.63 (m, H^(A)-CH₂); 1.80-1.97 (m, H^(B)- CH₂);2.52-2.90 (m, CH, 2x H^(A)-CH₂); 3.01-3.17 (m, H^(B)-CH₂); 3.19-3.28 (m,H^(B)-CH₂); 5.42 (q, CH); 6.68-6.82 (m, 2H-aromatic); 6.98-7.13 (m,1H-aromatic); 7.16-7.32 (m, 5H-aromatic) 72 CDCl₃; 1.43 (d, CH₃);1.52-1.68 (m, CH₂); 1.94-2.09 (m, H^(A)-CH₂); 2.09-2.25 (m, CH);2.25-2.38 (m, H^(B)-CH₂); 2.52-2.76 (m, CH₂); 2.74-2.81 (m, H^(A)-CH₂);3.10-3.22 (dt, H^(B)-CH₂); 5.43 (q, CH); 7.01-7.28 (m, 10H-aromatic) 73CDCl₃; 1.42 (d, CH₃); 1.40-1.66 (m, CH₂); 1.98-2.26 (m, CH, H^(A)- CH₂);2.27-2.44 (m, H^(B)-CH₂); 2.49-2.74 (m, CH₂); 2.78-2.90 (dt, H^(A)-CH₂);3.04-3.19 (m, H^(B)-CH₂); 5.41 (q, CH); 7.02-7.30 (m, 10H-aromatic) 74CDCl₃; 1.44 (d, CH₃); 1.51-1.70 (m, H^(A)-CH₂); 1.70-1.88 (m, H^(B)-CH₂); 1.97-2.13 (m, H^(A)-CH₂); 2.17-2.32 (m, CH); 2.34-2.50 (m,H^(B)-CH₂); 2.70-2.85 (q, H^(A)-CH₂); 3.04-3.25 (m, CH₂, H^(B)-CH₂);5.45 (q, CH); 7.08-7.31 (m, 7H-aromatic); 7.31-7.48 (m, 2H- aromatic);7.62 (m, 1H-aromatic); 7.75 (m, 1H-aromatic); 8.02 (m, 1H-aromatic) 75CDCl₃; 1.44 (d, CH₃); 1.48-1.66 (m, H^(A)-CH₂); 1.67-1.83 (m, H^(B)-CH₂); 2.02-2.20 (m, H^(A)-CH₂); 2.20-2.32 (m, CH); 2.40-2.57 (m,H^(B)-CH₂); 2.80-2.93 (dt, H^(A)-CH₂); 3.02-3.22 (m, CH₂, H^(B)-CH₂);5.43 (q, CH); 7.08-7.31 (m, 7H-aromatic); 7.32-7.49 (m, 2H- aromatic);7.63 (m, 1H-aromatic); 7.77 (m, 1H-aromatic); 8.01 (m, 1H-aromatic) 76CDCl₃; 1.39-1.83 (m, 2x CH₂); 1.53 (d, CH₃); 2.38 (s, 2x CH₃); 2.50-2.67(m, CH); 2.69-2.88 (m, 2x H^(A)-CH₂); 3.05-3.19 (m, H^(B)- CH₂);2.55-2.67 (dd, H^(B)-CH₂); 6.18 (q, CH); 7.00 (s, 3H- aromatic);7.17-7.34 (m, 5H-aromatic) 77 CDCl₃; 1.51 (d, CH₃); 1.38-1.84 (m, 2xCH₂); 2.38 (s, 2xCH₃); 100-104 2.50-2.67 (m, CH); 2.70-2.87 (m, 2xH^(A)-CH₂); 3.03-3.16 (m, H^(B)- CH₂); 3.51-3.62 (dd, H^(B)-CH₂); 6.17(q, CH); 7.01 (s, 3H- aromatic); 7.22-7.40 (m, 5H-aromatic) 78 CDCl₃;1.53 (d, CH₃); 1.37-1.88 (m, 2x CH₂); 2.77-2.99 (m, CH, H^(A)-CH₂);3.06-3.20 (m, H^(A)-CH₂, H^(B)-CH₂); 3.72-3.85 (dd, H^(B)- CH₂); 6.17(q, CH); 7.01-7.13 (m, 1H-aromatic); 7.18-7.40 (m, 7H-aromatic) 79CDCl₃; 1.45 (d, CH₃); 1.39-1.79 (m, 2x CH₂); 2.63-2.92 (m, CH, 121-125H^(A)-CH₂); 2.96-3.14 (m, H^(A)-CH₂, H^(B)-CH₂); 3.62-3.78 (dd, H^(B)-CH₂); 6.08 (q, CH); 6.98-7.07 (m, 1H-aromatic); 7.14-7.33 (m,7H-aromatic) 80 CDCl₃; 1.73-1.97 (m, CH₂); 2.78-3.06 (m, CH, CH₂,H^(A)-CH₂); 3.07-3.28 (m, CH₂); 3.37-3.67 (m, CH₂, H^(B)-CH₂); 6.90-7.32(m, 7H-aromatic) 81 CDCl₃; 1.73-1.98 (m, CH₂); 2.77-3.27 (m, CH, 2x CH₂,H^(A)-CH₂); 3.37-3.67 (m, CH₂, H^(B)-CH₂); 7.02-7.38 (m, 7H-aromatic) 82CDCl₃; 1.70-1.99 (m, CH₂); 2.73-3.25 (m, CH, 2x CH₂, H^(A)-CH₂);3.34-3.63 (m, CH₂, H^(B)-CH₂); 7.08 (m, 2H-aromatic); 7.27 (m, 2H-aromatic); 7.40 (m, 2H-aromatic) 83 CDCl₃; 1.48-1.63 (m, H^(A)-CH₂);1.76-1.92 (m, H^(B)-CH₂); 2.24 (s, 2x CH₃); 2.43-2.60 (m, CH,H^(A)-CH₂); 2.78 (t, CH₂); 2.95-3.25 (m, CH₂, H^(B)-CH₂); 3.37-3.61 (m,CH₂); 6.92 (s, 3H-aromatic); 7.08-7.27 (m, 5H-aromatic) 84 CDCl₃;1.57-1.75 (m, H^(A)-CH₂); 1.83-2.00 (m, H^(B)-CH₂); 2.55-2.90 (m, CH,CH₂, H^(A)-CH₂); 3.08-3.29 (m, CH₂, H^(B)-CH₂); 3.38-3.67 (m, CH₂);6.77-6.91 (m, 2H-aromatic); 7.08-7.34 (m, 6H- aromatic) 85 CDCl₃;1.52-1.70 (m, H^(A)-CH₂); 1.95-2.01 (m, H^(B)-CH₂); 70-71 2.63-2.78 (m,CH, H^(A)-CH₂); 2.83 (t, CH₂); 2.99-3.19 (m, CH₂); 3.20-3.34 (m,H^(B)-CH₂); 3.41-3.65 (m, CH₂); 6.83-6.93 (dt, 1H-aromatic); 7.08 (dd,1H-aromatic); 7.13-7.32 (m, 6H-aromatic) 86 CDCl₃; 1.48-1.63 (m,H^(A)-CH₂); 1.79-1.96 (m, H^(B)-CH₂); 2.53-2.67 (m, CH, H^(A)-CH₂);2.70-2.81 (t, CH₂); 2.92-3.20 (m, CH₂, H^(B)- CH₂); 3.34-3.58 (m, CH₂);5.85 (s, CH₂); 6.66 (s, 1H-aromatic); 6.73 (s, 1H-aromatic); 7.07-7.25(m, 5H-aromatic) 87 CDCl₃; 1.25-1.77 (m, 2x CH₂); 2.29 (s, CH₃);2.33-2.50 (m, CH, H^(A)-CH₂); 2.81 (dt, CH₂); 2.95-3.12 (m, CH₂);3.40-3.57 (m, CH₂, H^(B)-CH₂); 6.98-7.27 (m, 9H-aromatic) 88 CDCl₃;1.22-1.78 (m, 2x CH₂); 2.43-2.59 (m, CH); 2.60-2.74 (m, 104-105H^(A)-CH₂); 2.74-2.88 (t, CH₂); 2.93-3.09 (m, CH₂); 3.37-3.55 (m, CH₂,H^(B)-CH₂); 6.82 (dt, 1H-aromatic); 7.00 (dd, 1H-aromatic); 7.08-7.27(m, 6H-aromatic) 89 CDCl₃; 1.53-1.70 (m, H^(A)-CH₂); 1.88-2.02 (m,H^(B)-CH₂); 87.5-89.5 2.49-2.68 (m, CH, H^(A)-CH₂); 2.80 (t, CH₂);2.91-3.13 (m, CH₂, H^(B)-CH₂); 3.39-3.62 (m, CH₂); 5.90 (s, CH₂);6.58-6.73 (m, 3H-aromatic); 7.12-7.32 (m, 5H-aromatic) 90 mixture of 2diastereoisomers 91 CDCl₃; 1.52 (d, CH₃); 2.45-2.66 (m, H^(A)-CH₂);2.00-2.21 (m, H^(B)- CH₂); 2.28 (s, 2x CH₃); 2.67-2.87 (m, CH,H^(A)-CH₂); 3.19-3.31 (dt, H^(B)-CH₂); 3.46-3.62 (m, CH); 5.51 (q, CH);5.57 (s, OH); 6.92 (s, 1H-aromatic); 6.99 (d, 1H-aromatic); 7.19-7.38(m, 5H-aromatic) 7.43 (d, 1H-aromatic) 92 CDCl₃; 1.72-1.97 (m, CH₂);2.75-3.26 (m, CH, 2x CH₂, H^(A)-CH₂); 3.39-3.62 (m, CH₂, H^(B)-CH₂);3.78 (s, CH₃); 6.84 (m. 2H- aromatic); 7.08-7.19 (m, 3H-aromatic); 7.28(d, 2H-aromatic) 93 CDCl₃; 1.72-1.90 (m, CH₂); 2.30 (s, CH₃); 2.75-2.88(t, CH₂); 2.88-3.27 (m, CH, CH₂, H^(A)-CH₂); 3.38-3.48 (dd, H^(B)-CH₂);3.48-3.60 (m, CH₂); 7.00-7.16 (m, 5H-aromatic); 7.25 (d, 2H-aromatic) 94CDCl₃; 0.89 (t, CH₃); 1.66-1.99 (m, CH₂, H^(A)-CH₂, H^(B)-CH₂);2.69-2.89 (m, CH, H^(A)-CH₂); 2.99 (m, H^(A)-CH₂); 3.19 (m, H^(B)-CH₂);3.43 (dd, H^(B)-CH₂); 5.15 (t, CH); 6.98 (t, 1H-aromatic); 7.22 (7H-aromatic) 95 CDCl₃; 0.94 (t, CH₃); 1.64-2.11 (m, 2x CH₂); 2.90-3.08 (m,CH, 2x H^(A)-CH₂); 3.08-3.21 (m, H^(B)-CH₂); 3.42-3.58 (m, H^(B)-CH₂);5.23 (q, CH); 7.07 (t, 1H-aromatic); 7.20-7.38 (m, 7H-aromatic) 96CDCl₃; 0.91 (t, CH₃); 1.70-1.82 (m, CH₂); 1.82-2.01 (m, CH₂); 2.71-2.92(m, CH, H^(A)-CH₂); 2.94-3.08 (m, H^(A)-CH₂); 3.16-3.28 (m, H^(B)-CH₂);3.40-3.50 (dd, H^(B)-CH₂); 5.17 (q, CH); 7.00 (t, 1H- aromatic);7.12-7.27 (m, 7H-aromatic) 97 CDCl₃; 0.85 (t, CH₃); 1.57-2.00 (m, 2xCH₂); 2.82-2.99 (m, CH, 2x H^(A)-CH₂); 2.99-3.11 (m, H^(B)-CH₂);3.32-3.49 (m, H^(B)-CH₂); 5.14 (q, CH); 6.98 (t, 1H-aromatic); 7.11-7.29(m, 7H-aromatic) 98 CDCl₃; 1.81-1.96 (m, CH₂); 2.85-3.17 (m, CH, 2xH^(A)-CH₂); 3.37-3.55 (m, 2x H^(B)-CH₂); 3.44 (s, CH₃); 3.77-3.87 (m,H^(A)-CH₂); 3.89-4.00 (m, H^(B)-CH₂); 5.50 (q, CH); 7.09 (t,1H-aromatic); 7.20-7.38 (m, 7H-aromatic) 99 CDCl₃, 1.73-2.00 (m,H^(A)-CH₂, H^(B)-CH₂); 2.92-3.34 (m, CH, CH₂, H^(A)-CH₂); 3.40 (s, CH₃);3.42-3.60 (m, H^(B)-CH₂); 3.76-3.97 (m, CH₂); 5.49 (dd, CH); 7.02-7.11(m, 1H-aromatic); 7.21-7.40 (m, 7H-aromatic) 100 CDCl₃; 1.81-1.97 (m,CH₂); 2.85-3.18 (m, CH, 2x H^(A)-CH₂); 3.38-3.57 (m, 2x H^(B)-CH₂); 3.43(s, CH₃); 3.77-3.88 (m, H^(A)-CH₂); 3.90-4.01 (m, H^(B)-CH₂); 5.50 (q,CH); 7.07 (t, 1H-aromatic); 7.20-7.39 (m, 7H-aromatic) 101 CDCl₃;1.73-2.02 (m, CH₂); 2.95-3.60 (m, CH, 2x H^(A)-CH₂, 2x H^(B)- CH₂); 3.40(s, CH₃); 3.74-3.85 (m, H^(A)-CH₂); 3.88-3.98 (m, H^(B)- CH₂); 5.50 (q,CH); 7.07 (t, 1H-aromatic); 7.21-7.40 (m, 7H- aromatic) 102 contains 10%from isomer LIB-90-B CDCl₃; 1.60-1.86 (m, CH₂); 2.62-3.50 (m, CH, 3xH^(A)-CH₂, 3x H^(B)- CH₂); 5.67 (q, CH); 7.02 (t, 1H-aromatic);7.11-7.43 (m, 12H- aromatic) 103 mixture of diastereoisomers A and BCDCl₃; 1.50-1.83 (m, CH₂); 2.48-3.45 (m, CH, 3x H^(A)-CH₂, 3x H^(B)-CH₂); 5.61-5.80 (m, CH); 7.00 (t, 1H-aromatic); 7.11-7.43 (m,12H-aromatic) 104 CDCl₃; 1.83-1.98 (m, CH₂); 2.92-3.20 (m, CH, 2xH^(A)-CH₂); 3.29-3.42 (m, H^(B)-CH₂); 3.42-3.58 (m, H^(B)-CH₂); 3.72 (s,OH); 3.98-4.12 (m, H^(A)-CH₂); 4.12-4.26 (m, H^(B)-CH₂); 5.02 (q, CH);7.08 (t, 1H- aromatic); 7.22-7.40 (m, 7H-aromatic) 105 CDCl₃; 1.80 (m,CH₂); 2.97-3.33 (m, H^(A)-CH₂, CH, CH₂), 3.41-3.58 (m, H^(B)-CH₂); 3.91(t, OH); 3.98-4.21 (m, CH₂), 5.04 (q, CH), 7.08 (t, 1H-aromatic);7.19-7.42 (m, 7H-aromatic) 106 CDCl₃; 1.82-2.01 (m, CH₂); 2.93-3.20 (m,CH, 2x H^(A)-CH₂); 3.27-3.40 (m, H^(B)-CH₂); 3.46-3.61 (m, OH,H^(B)-CH₂); 3.98-4.11 (m, H^(A)- CH₂); 4.12-4.27 (m, H^(B)-CH₂); 4.97(q, CH); 7.10 (t, 1H-aromatic); 7.21-7.42 (m, 7H-aromatic) 107 CDCl₃;1.78-2.04 (m, CH₂); 2.96-3.34 (m, CH, 2x H^(A)-CH₂, H^(B)- CH₂);3.41-3.59 (m, H^(B)-CH₂); 3.84-3.97 (m, OH); 3.08-4.21 (m, CH₂); 5.05(q, CH); 7.09 (t, 1H-aromatic); 7.18-7.42 (m, 7H- aromatic) 108 CDCl₃;1.50-1.70 (m, H^(A)-CH₂); 1.88-2.05 (m, H^(B)-CH₂); 2.56-2.73 (m, CH,H^(A)-CH₂); 2.73-2.88 (t, CH₂); 2.94-3.23 (m, H^(A)-CH₂, 2x H^(B)-CH₂);3.39-3.63 (m, CH₂); 6.68-6.85 (m, 2H-aromatic); 7.07-7.32 (m,6H-aromatic) 109 CDCl₃; 1.52-1.70 (m, H^(A)-CH₂); 1.85-2.01 (m,H^(B)-CH₂); 2.50-2.69 (m, CH, H^(A)-CH₂); 2.72-2.85 (t, CH₂); 2.86-2.99(dt, H^(A)-CH₂); 2.99-3.13 (m, 2x H^(B)-CH₂); 3.41-3.58 (m, CH₂); 3.85(s, CH₃); 5.11 (s, CH₂); 6.62 (dd, 1H-aromatic); 6.77 (d, 2H-aromatic);7.10-7.46 (m, 10H-aromatic) 110 CDCl₃; 1.58-1.77 (m, H^(A)-CH₂);1.80-1.96 (m, CH₂); 1.96-2.11 (m, H^(B)-CH₂); 2.36 (s, CH₃); 2.47-2.79(m, CH, CH₂, H^(A)-CH₂); 3.18-3.29 (m, H^(A)-CH₂, H^(B)-CH₂); 3.30-3.43(m, CH₂, H^(B)-CH₂); 7.08-7.34 (m, 9H-aromatic) 111 CDCl₃; 1.60-2.07 (m,CH₂, H^(A)-CH₂, H^(B)-CH₂); 2.56-2.68 (t, CH₂); 2.71-2.88 (m, CH,H^(A)-CH₂); 3.13-3.27 (m, H^(A)-CH₂, H^(B)-CH₂); 3.29-3.48 (m, CH₂,H^(B)-CH₂); 7.08-7.40 (m, 9H-aromatic) 112 CDCl₃; 1.57-1.74 (m,H^(A)-CH₂); 1.76-1.92 (m, CH₂); 1.92-2.08 (m, H^(B)-CH₂); 2.61 (t, CH₂);2.68-2.87 (m, CH, H^(A)-CH₂); 3.13-3.27 (m, H^(A)-CH₂, H^(B)-CH₂);3.28-3.42 (m, CH₂, H^(B)-CH₂); 6.82-6.96 (dt, 1H-aromatic); 7.03-7.33(m, 7H-aromatic) 113 CDCl₃; 1.61-1.79 (m, H^(A)-CH₂); 1.81-2.08 (m, CH₂,H^(B)-CH₂); 2.38 (s, 2x CH₃); 2.58-2.73 (m, CH, CH₂, H^(A)-CH₂);3.15-3.46 (m, CH₂, H^(A)-CH₂, 2x H^(B)-CH₂); 7.04 (s, 3H-aromatic);7.13-7.35 (m, 5H- aromatic) 114 CDCl₃; 1.76-2.00 (m, 2x CH₂); 2.63 (t,CH₂); 2.82-3.55 (m, CH, 3x CH₂); 7.01-7.36 (m, 8H-aromatic) 115 CDCL₃;1.77 (s, CH₃); 1.79 (s, CH₃); 1.88 (m, CH₂); 2.82-2.97 (m, CH); 3.05 (t,H^(A)-CH₂); 3.18-3.40 (m, CH₂); 3.45 (dd, H^(B)-CH₂); 7.07 (t,1H-aromatic); 7.17-7.39 (m, 7H-aromatic) 116 CDCl₃; 1.52 (d, CH₃);1.78-2.17 (m, 3x CH₂); 2.82-3.19 (m, 2x CH₂, H^(A)-CH₂); 3.20-3.37 (m,H^(B)-CH₂); 5.62 (q, CH); 7.10-7.50 (m, 13H-aromatic); 7.55-7.67 (m,2H-aromatic); 7.69-7.80 (m, 2H- aromatic); 7.93 (d, 1H-aromatic); 8.01(d, 1H-aromatic) 117 mixture of 2 diastereoisomers CDCl₃; 1.10 (d, 0.4xCH₃); 1.45 (d, 0.6x CH₃); 1.55 (s, 0.6x CH₃); 1.62 (s, 0.4x CH₃);1.50-1.97 (m, CH₂); 2.48-3.66 (m, CH, 3x CH₂); 4.70-5.19 (OH); 5.26 (q,0.4 CH); 5.43 (q, 0.6x CH); 6.97-7.44 (m, 9H-aromatic) 118 2diastereoisomers 119 CDCl₃; 1.51 (d, CH₃); 1.60-1.79 (m, HA -CH₂);1.85-2.00 (m, H^(B)- CH₂); 2.68-2.89 (m, CH, 2x H^(A)-CH₂); 3.17 (dt,H^(B)-CH₂); 3.36 (d, H^(B)-CH₂); 3.85 (s, 2x CH₃); 5.52 (q, CH); 6.78(d, 1H-aromatic); 7.00 (d, 1H-aromatic); 7.29 (m, 5H-aromatic) 120CDCl₃; 1.51 (d, CH₃); 1.60 (m, H^(A)-CH₂); 1.98 (m, H^(B)-CH₂);2.68-2.93 (m, CH, 2x H^(A)-CH₂); 3.16 (m, H^(B)-CH₂); 3.40 (dd,H^(B)-CH₂); 3.84 (s, 2x CH₃); 5.49 (q, CH); 6.72 (d, 1H-aromatic); 6.97(d, 1H- aromatic); 7.28 (m, 5H-aromatic) 121 CDCl₃; 1.50 (d, CH₃);1.55-1.70 (m, H^(A)-CH₂); 1.91-2.08 (m, H^(B)- CH₂); 2.60-2.89 (m, CH,2x H^(A)-CH₂); 3.06-3.23 (m, H^(B)-CH₂); 3.84 (s, CH₃); 5.12 (s, CH₂);5.49 (q, CH); 6.58-6.68 (dd, 1H- aromatic); 6.71-6.82 (m, 2H-aromatic);7.16-7.48 (m, 10H- aromatic) 122 CDCl₃; 1.43 (d, CH₃); 1.59-1.77 (m,H^(A)-CH₂); 1.83-2.01 (m, H^(B)- CH₂); 2.61-2.83 (m, CH, 2x H^(A)-CH₂);2.93-3.20 (m, 2x H^(B)-CH₂); 3.87 (s, CH₃); 5.12 (s, CH₂); 5.51 (q, CH);6.61-6.72 (dd, 1H- aromatic); 6.73-6.83 (m, 2H-aromatic); 7.17-7.45 (m,10H- aromatic) 123 CDCl₃; 1.50 (d, CH₃); 1.56-1.86 (m, CH₂); 2.02-2.47(m, CH, CH₂); 2.59-2.90 (m, H^(A)-CH₂, CH₂); 3.18-3.31 (dt, H^(B)-CH₂);3.79 (s, CH₃); 5.51 (q, CH); 6.87-6.91 (m, 2H-aromatic); 7.08-7.36 (m,7H-aromatic) 124 CDCl₃; 1.49 (d, CH₃); 1.52-1.69 (m, CH₂); 2.08-2.33 (m,CH, H^(A)- CH₂); 2.37-2.52 (m, H^(B)-CH₂); 2.58-2.79 (m, CH₂); 2.83-2.98(dt, H^(A)-CH₂); 3.12-3.27 (m, H^(B)-CH₂); 3.78 (s, CH₃); 5.49 (q, CH);6.74-6.90 (m, 2H-aromatic); 7.08-7.38 (m, 7H-aromatic) 125 CDCl₃; 1.43(d, CH₃); 1.48-1.68 (m, CH₂); 1.93-2.22 (m, CH, H^(A)- CH₂); 2.23-2.39(m, H^(B)-CH₂); 2.48-2.70 (m, CH₂); 2.70-2.82 (m, H^(A)-CH₂); 3.10-3.22(dt, H^(B)-CH₂); 3.75 (s, CH₃); 3.78 (s, CH₃); 5.42 (q, CH); 6.60-6.72(m, 3H-aromatic); 7.10-7.27 (m, 5H- aromatic) 126 CDCl₃; 1.48 (d, CH₃);1.45-1.70 (m, CH₂); 2.04-2.38 (m, CH, H^(A)- CH₂); 2.35-2.51 (m,H^(B)-CH₂); 2.52-2.74 (m, CH₂); 2.85-2.97 (dt, H^(A)-CH₂); 3.12-3.26 (m,H^(B)-CH₂); 3.81 (s, CH₃); 3.84 (s, CH₃); 5.46 (q, CH); 6.67-6.79 (m,3H-aromatic); 7.17-7.35 (m, 5H- aromatic) 127 CDCl₃; 1.56 (d, CH₃);1.60-1.79 (m, CH₂); 2.08-2.29 (m, CH, H^(A)- CH₂); 2.37 (s, CH₃);2.39-2.54 (m, H^(B)-CH₂); 2.69-2.80 (t, CH₂); 2.82-2.97 (m, H^(A)-CH₂);3.23-3.36 (dt, H^(B)-CH₂); 5.56 (q, CH); 7.07-7.22 (m, 4H-aromatic);7.22-7.40 (m, 5H-aromatic) 128 CDCl₃; 1.55 (d, CH₃); 1.55-1.75 (m, CH₂);2.10-2.30 (m, CH, H^(A)- CH₂); 2.35 (s, CH₃); 2.46-2.61 (m, H^(B)-CH₂);2.66-2.78 (t, CH₂); 2.90-3.03 (dt, H^(A)-CH₂); 3.18-3.32 (m, H^(B)-CH₂);5.55 (q, CH); 7.04-7.22 (m, 4H-aromatic); 7.23-7.40 (m, 5H-aromatic) 129CDCl₃; 1.44 (d, CH₃); 1.33-1.62 (m, CH₂); 2.06-2.24 (m, CH, H^(A)- CH₂);2.33-2.44 (dq, H^(B)-CH₂); 2.71-2.92 (m, CH₂, H^(A)-CH₂); 3.09-3.22 (m,H^(B)-CH₂); 5.41 (q, CH); 6.80-6.92 (m, 1H-aromatic); 6.93-7.11 (m,2H-aromatic); 7.13-7.30 (m, 5H-aromatic) 130 CDCl₃; 1.53 (d, CH₃);1.56-1.76 (m, CH₂); 2.02-2.19 (m, H^(A)-CH₂); 2.19-2.32 (m, CH);2.32-2.49 (m, H^(B)-CH₂); 2.53-2.78 (m, CH₂); 2.78-2.93 (m, H^(A)-CH₂);2.92 (s, 2x CH₃); 3.20-3.32 (dt, H^(B)-CH₂); 5.54 (q, CH); 6.71 (d,2H-aromatic); 7.11 (d, 2H-aromatic); 7.22-7.39 (m, 5H-aromatic) 131CDCl₃; 1.51 (d, CH₃); 1.50-1.71 (m, CH₂); 2.08-2.33 (m, CH, H^(A)- CH₂);2.38-2.53 (m, H^(B)-CH₂); 2.53-2.76 (m, CH₂); 2.85-2.99 (m, H^(A)-CH₂);2.92 (s, 2x CH₃); 3.13-3.28 (m, H^(B)-CH₂); 5.51 (q, CH); 6.70 (d,2H-aromatic); 7.10 (d, 2H-aromatic); 7.21-7.39 (m, 5H- aromatic) 132CDCl₃; 1.52 (d, CH₃); 1.56-1.73 (m, CH₂); 2.01-2.17 (m, H^(A)-CH₂);2.17-2.29 (m, CH); 2.30-2.46 (m, H^(B)-CH₂); 2.54-2.77 (m, CH₂);2.78-2.90 (m, H^(A)-CH₂); 3.19-3.31 (dt, H^(B)-CH₂); 3.77 (s, CH₃); 5.52(q, CH); 6.82 (d, 2H-aromatic); 7.13 (d, 2H-aromatic); 7.20-7.38 (m,5H-aromatic) 133 CDCl₃; 1.49 (d, CH₃); 1.48-1.69 (m, CH₂); 2.04-2.32 (m,CH, H^(A)- CH₂); 2.33-2.50 (m, H^(B)-CH₂); 2.51-2.76 (m, CH₂); 2.84-2.97(dt, H^(A)-CH₂); 3.11-3.26 (m, H^(B)-CH₂); 3.75 (s, CH₃); 5.48 (q, CH);6.81 (d, 2H-aromatic); 7.11 (d, 2H-aromatic); 7.18-7.37 (m, 5H-aromatic) 134 CDCL₃; 1.31 (d, CH₃); 1.52 (d, CH₃); 1.61 (m, CH₂);1.98-2.16 (m, CH, H^(A)-CH₂); 2.36 (dt, H^(B)-CH₂); 2.68-2.90 (m, CH,H^(A)-CH₂); 3.22 (dt, H^(B)-CH₂); 5.50 (q, CH); 7.12-7.38 (m,10H-aromatic) 135 CDCl₃; 1.19 (d, CH₃); 1.24 (m, H^(A)-CH₂); 1.39 (d,CH₃); 1.45 (m, H^(B)-CH₂); 1.77 (m, H^(A)-CH₂); 2.10-2.21 (m,H^(B)-CH₂); 2.25-2.39 (m, CH); 2.74 (dt, H^(A)-CH₂); 2.87 (m, CH); 3.02(m, H^(B)-CH₂); 5.39 (q, CH); 7.03-7.27 (m, 10H aromatic) 136 CDCl₃;1.28 (d, CH₃); 1.37-1.65 (m, CH₂); 1.49 (d, CH₃); 1.73-1.92 (m,H^(A)-CH₂); 2.17-2.43 (m, CH, H^(B)-CH₂); 2.68-2.81 (m, H^(A)- CH₂);2.85-3.02 (m, CH); 3.09-3.21 (dt, H^(B)-CH₂); 5.50 (q, CH); 7.12-7.37(m, 10H-aromatic) 137 CDCl₃; 1.30 (d, CH₃), 1.44 (d, CH₃); 1.5 (m, CH₂);2.01-2.21 (m, CH, H^(A)-CH₂); 2.27-2.42 (dt, H^(B)-CH₂); 2.68-2.82 (m,CH); 2.83-2.95 (dt, H^(A)-CH₂), 3.05-3.19 (m, H^(B)-CH₂); 5.46 (q, CH);7.15-7.38 (m, 10H-aromatic) 138 CDCl₃; 0.77 (t, CH₃); 1.20-1.85 (m, 2xCH₂, H^(A)-CH₂); 1.48 (d, CH₃); 2.19-2.39 (m, CH, H^(B)-CH₂); 2.61-2.79(m, CH, H^(A)-CH₂); 3.03-3.18 (m, H^(B)-CH₂); 5.48 (q, CH); 7.11-7.37(m, 10H-aromatic) 139 CDCl₃; 0.80 (t, CH₃); 1.51 (d, CH₃); 1.51-1.78 (m,2x CH₂); 2.01 (m, CH, H^(A)-CH₂); 2.35 (dt, H^(B)-CH₂); 2.47 (m, CH);2.72 (m, H^(A)- CH₂); 3.20 (dt, H^(B)-CH₂); 5.49 (q, CH); 7.13-7.32(10H-aromatic) 140 mixture of 3 diastereoisomers CDCL₃, 0.70-0.84 (m,CH₃); 1.18-1.84 (m, 2x CH₂, CH₃); 1.93-2.18 (m, H^(A)-CH₂, 0.6x CH);2.23-2.55 (m, H^(B)-CH₂, 0.4x CH, 0.7x CH); 2.67-3.94 (m, H^(A)-CH₂,0.3x CH); 3.00-3.26 (m, H^(B)-CH₂); 5.39-5.55 (m, CH); 7.10-7.40 (m,10H-aromatic) 141 CDCl₃; 0.79 (t, CH₃); 1.17-1.82 (m, 2x CH₂); 1.43 (d,CH₃); 1.98-2.08 (m, CH, H^(A)-CH₂); 2.25-2.52 (m, CH, H^(B)-CH₂);2.82-2.95 (m, H^(A)-CH₂); 3.00-3.18 (m, H^(B)-CH₂); 5.45 (q, CH);7.12-7.39 (m, 10H-aromatic) 142 CDCl₃; 1.12 (s, CH₃); 1.27 (d, CH₃);1.43-1.60 (m, H^(A)-CH₂); 1.79-1.92 (m, H^(B)-CH₂); 2.27 (s, CH₃);2.51-2.62 (m, CH₂); 2.73 (d, H^(A)- CH₂); 2.96 (d, H^(B)-CH₂); 5.40 (q,CH); 6.97-7.24 (m, 9H-aromatic) 143 CDCl₃; 1.16 (s, CH₃); 1.39 (d, CH₃);1.49-1.61 (m, H^(A)-CH₂); 1.65-1.80 (m, H^(B)-CH₂); 2.19 (s, CH₃);2.41-2.52 (dt, H^(A)-CH₂); 2.70 (d, H^(A)-CH₂); 2.96 (d, H^(B)-CH₂);2.97-3.09 (m, H^(A)-CH₂); 5.36 (q, CH); 6.88-7.22 (m, 9H-aromatic) 144CDCl₃; 0.81 (t, CH₃); 1.20 (d, CH₃); 1.40-1.78 (m, 2x CH₂); 2.25 (s,CH₃); 2.27-2.39 (m, H^(A)-CH₂); 2.43-2.57 (m, H^(B)-CH₂); 2.72 (d,H^(A)-CH₂); 2.97 (d, H^(B)-CH₂); 5.41 (q, CH); 6.94-7.27 (m, 9H-aromatic) 145 CDCl₃; 0.97 (t, CH₃); 1.46 (d, CH₃); 1.52-1.89 (m, 2xCH₂); 2.25 (s, CH₃); 2.30-2.47 (m, H^(A)-CH₂); 2.74 (d, H^(A)-CH₂);2.98-3.13 (m, H^(B)-CH₂); 3.10 (d, H^(B)-CH₂); 5.48 (q, CH); 6.90-7.27(m, 9H- aromatic) 146 mixture of 2 diastereoisomers CDCl₃; 0.79-0.93 (m,CH₃); 1.19 (d, 0.7x CH₃); 1.38 (d, 0.3x CH₃); 1.08-1.79 (m, 3x CH₂);2.17 (s, 0.3x CH₃); 2.25 (s, 0.7x CH₃); 2.27-2.38 (m, H^(A)-CH₂);2.43-2.57 (m, H^(B)-CH₂); 2.60-2.77 (m, H^(A)-CH₂); 2.89-3.07 (m,H^(B)-CH₂); 5.40 (q, CH); 6.92-7.28 (m, 9H-aromatic) 147 mixture of 2diastereoisomers 148 CDCl₃; 1.48 (d, CH₃); 1.53-1.69 (m, H^(A)-CH₂);1.74-1.90 (m, H^(B)- CH₂); 2.29 (s, 2x CH₃); 2.49-2.78 (m, CH, 2xH^(A)-CH₂); 3.12-3.31 (m, 2x H^(B)-CH₂); 5.47 (q, CH); 6.93 (s,3H-aromatic); 7.11-7.30 (m, 5H-aromatic) 149 CDCl₃; 1.44 (d, CH₃);1.40-1.60 (m, H^(A)-CH₂); 1.80-1.96 (m, H^(B)- CH₂); 2.25 (s, 2x CH₃);2.49-2.67 (m, CH, H^(A)-CH₂); 2.81-2.92 (dt, H^(A)-CH₂); 3.00-3.13 (m,H^(B)-CH₂); 3.21-3.36 (m, H^(B)-CH₂); 5.43 (q, CH); 6.91 (s,3H-aromatic); 7.13-7.32 (m, 5H-aromatic) 150 CDCl₃; 1.51 (d, CH₃);1.59-1.78 (m, H^(A)-CH₂); 1.87-2.02 (m, H^(B)- CH₂); 2.70-2.89 (m, CH,2x H^(A)-CH₂); 3.10-3.23 (dt, H^(B)-CH₂); 3.28-3.43 (m, H^(B)-CH₂); 5.51(q, CH); 6.87-6.98 (dt, 1H-aromatic); 7.10 (dd, 1H-aromatic); 7.21-7.38(m, 6H-aromatic) 151 CDCl₃; 1.50 (d, CH₃); 1.50-1.67 (m, H^(A)-CH₂);1.92-2.08 (m, H^(B)- CH₂); 2.73-2.93 (m, CH, 2x H^(A)-CH₂); 3.12-3.25(m, H^(B)-CH₂); 3.28-3.44 (m, H^(B)-CH₂); 5.49 (q, CH); 6.80-6.91 (dt,1H-aromatic); 7.08 (dd, 1H-aromatic); 7.19-7.38 (m, 6H-aromatic) 152CDCl₃; 1.46 (d, CH₃); 1.59-1.76 (m, H^(A)-CH₂); 1.87-2.02 (m, H^(B)-CH₂); 2.59-2.86 (m, CH, 2x H^(A)-CH₂); 2.99-3.18 (m, 2x H^(B)-CH₂); 5.51(q, CH); 5.91 (s, CH₂); 6.60-6.75 (m, 3H-aromatic); 7.19-7.38 (m,5H-aromatic) 153 contains 8% from isomer LIB-59-A CDCl₃; 1.50 (d, CH₃);1.48-1.67 (m, H^(A)-CH₂); 1.89-2.08 (m, H^(B)- CH₂); 2.58-2.87 (m, CH,2x H^(A)-CH₂); 3.04-3.22 (m, 2x H^(B)-CH₂); 5.49 (q, CH); 5.90 (s, CH₂);6.59-7.75 (m, 3H-aromatic); 7.18-7.37 (m, 5H-aromatic) 154 CDCl₃; 1.43(d, CH₃); 1.55-1.72 (m, H^(A)-CH₂); 1.78-1.93 (m, H^(B)- CH₂); 2.60-2.81(m, CH, 2x H^(A)-CH₂); 3.04-3.28 (m, 2x H^(B)-CH₂); 5.44 (q, CH); 5.86(s, CH₂); 6.69 (s, 1H-aromatic); 6.73 (s, 1H- aromatic); 7.12-7.30 (m,5H-aromatic) 155 CDCl₃; 1.43 (d, CH₃); 1.45-1.58 (m, H^(A)-CH₂);1.83-1.99 (m, H^(B)- CH₂); 2.58-2.86 (m, CH, 2x H^(A)-CH₂); 3.03-3.18(m, H^(B)-CH₂); 3.18-3.27 (dd, H^(B)-CH₂); 5.41 (q, CH); 5.85 (s, CH₂);6.69 (s, 1H- aromatic); 6.71 (s, 1H-aromatic); 7.11-7.29 (m,5H-aromatic) 156 CDCl₃; 1.51 (d, CH₃); 1.55-1.72 (m, CH₂); 1.91-2.08 (m,H^(A)-CH₂); 2.37-2.57 (m, CH, H^(B)-CH₂); 2.72-2.87 (m, H^(A)-CH₂);3.14-3.28 (m, H^(B)-CH₂); 3.19 (s, CH₃); 4.34 (m, CH); 5.50 (q, CH);7.20-7.39 (m, 10H-aromatic) 157 CDCl₃; 1.50 (d, CH₃); 1.51-1.68 (m,H^(A)-CH₂); 1.72-1.88 (m, H^(B)- CH₂); 2.10-2.23 (m, CH, H^(A)-CH₂);2.43-2.58 (m, H^(B)-CH₂); 2.85-2.95 (dt, H^(A)-CH₂); 3.12-3.23 (m,H^(B)-CH₂); 3.21 (s, CH₃); 4.43 (dd, CH); 5.46 (q, CH); 7.19-7.38 (m,10H-aromatic) 158 CDCl₃; 1.23 (d, CH₃); 1.35 (d, CH₃); 1.73 (m, CH₂);2.65 (m, CH, H^(A)-CH₂); 2.91 (m, H^(B)-CH₂); 3.37 (m, CH); 5.44 (q,CH); 7.18 (m, 10H-aromatic) 159 CDCl₃; 1.14 (d, CH₃); 1.35 (d, CH₃);1.50-1.65 (m, H^(A)-CH₂); 1.65-1.80 (m, H^(B)-CH₂), 2.39-2.62 (m, CH,CH₂); 3.23-3.38 (m, CH); 5.33 (q, CH); 7.05-7.23 (m, 10H-aromatic) 160CDCl₃; 1.15 (d, CH₃); 1.41 (d, CH₃); 1.63-1.78 (m, CH₂); 2.68-2.80 (m,CH, H^(A)-CH₂); 3.00-3.13 (m, H^(B)-CH₂); 3.38-3.50 (m, CH); 5.44 (q,CH); 7.03-7.30 (m, 10H-aromatic) 161 CDCl₃; 1.36 (d, CH₃); 1.37 (d,CH₃); 1.41-1.59 (m, H^(A)-CH₂); 1.72-1.90 (m, H^(B)-CH₂); 2.32-2.47 (dt,CH); 2.57-2.70 (m, H^(A)-CH₂); 2.89-3.02 (m, H^(B)-CH₂); 3.25-3.39 (m,CH); 5.32 (q, CH); 6.82-6.94 (m, 2H-aromatic); 7.01-7.20 (m,8H-aromatic) 162 CDCl₃; 1.27 (d, 0.65x CH₃); 1.44 (d, 0.35x CH₃); 1.52(d, 0.35x CH₃); 1.55 (d, 0.65x CH₃); 1.65-2.02 (m, CH₂); 2.38 (s, 0.35xCH₃); 2.43 (s, 0.65x CH₃); 2.62-2.87 (m, CH, H^(A)-CH₂); 2.97-3.08 (m,0.35x H^(B)-CH₂); 3.13-3.26 (m, 0.65x H^(B)-CH₂); 3.27-3.39 (m, 0.35xCH); 3.74-3.88 (m, 0.65x CH); 5.47-5.62 (m, CH); 7.05-7.39 (m,9H-aromatic) 163 CDCl₃; 1.09 (d, 0.8x CH₃); 1.40 (d, 0.2x CH₃); 1.42 (d,CH₃); 1.57-1.87 (m, CH₂); 2.19 (s, 0.2x CH₃); 2.32 (s, 0.8x CH₃);2.57-2.70 (m, CH, 0.2x H^(A)-CH₂); 2.74-2.87 (dt, 0.8x H^(A)-CH₂);2.92-3.20 (m, 0.2x CH, H^(B)-CH₂); 3.66-3.78 (m, 0.8x CH); 5.32-5.51 (m,CH); 6.90-7.29 (m, 9H-aromatic) 164 CDCl₃; 1.84 (m, CH₂); 2.15 (m, CH₂);2.43-2.59 (m, 2x CH₂); 3.05-3.27 (m, 2x CH₂); 3.86 (s, 2x CH₃); 5.12 (s,2x CH₂); 6.66 (dd, 2H-aromatic); 6.73-6.84 (m, 4H-aromatic); 6.89-6.99(m, 2H- aromatic) 7.11-7.46 (m, 13H-aromatic) 165 mixture ofdiastereoisomers 166 CDCl₃; 1.54 (d, 3H, CH₃); 1.60 (s, 3H, CH₃);1.96-2.14 (m, 1H, H^(A)-CH₂); 2.28-2.41 (m, 1H, H^(B)-CH₂); 2.84-2.93(m, 1H, H^(A)- NCH₂); 3.12-3.31 (m, H^(B)-NCH₂); 5.58 (m, CH); 7.28-7.54(m, 10H-aromatic) 167 CDCl₃; 1.54 (d, 3H, CH₃); 1.60 (s, 3H, CH₃);1.96-2.14 (m, 1H, H^(A)-CH₂); 2.28-2.41 (m, 1H, H^(B)-CH₂); 2.84-2.93(m, 1H, H^(A)- NCH₂); 3.12-3.31 (m, H^(B)-NCH₂); 5.58 (m, CH); 7.28-7.54(m, 10H-aromatic)

C. Pharmacological Examples Example C.1 Enzymatic Assays to Test theEffect of Compounds on 11b-Hydroxysteroid Dehydrogenase Type 1 and Type2

The effects of compounds on 11b-HSD1 dependent conversion of cortisoneinto cortisol (reductase activity) was studied in a reaction mixturecontaining 30 mM Tris-HCl buffer pH 7.2, 180 μM NADPH, 1 mM EDTA, 2 μMcortisone, 1 μl drug and/or solvent and 11 μg recombinant protein in afinal volume of 100 μl.

The effect on the 11b-HSD1-dehydrogenase activity (conversion ofcortisol into cortisone) was measured in a reaction mixture containing0.1M sodium phosphate buffer pH 9.0, 300 μM NADP, 25 μM cortisol, 1 μldrug and/or solvent and 3.5 μg recombinant protein in a final volume of100 μl.

The effects on the 11b-HSD2 dependent dehydrogenase activity was studiedin a reaction mixture containing 0.1M sodium phosphate buffer pH 7.5,300 μM NAD, 100 nM cortisol (of which 2 nM is 3H-radio labelled), 1 μldrug and/or solvent and 2.5 μg recombinant protein in a final volume of100 μl.

All incubations were performed for 45 min at 37 C in a water bath. Thereaction was stopped by adding 100 μl acetonitrile containing 20 μgcorticosterone as internal standard. After centrifugation, the productformation was analysed in the supernatant by HPLC on a Hypersyl BDS-C18column using 0.05 mM ammonium acetate/methanol (50/50) as solvent. Inall of the aforementioned assays, the drugs to be tested were taken froma stock solution and tested at a final concentration ranging from −10⁻⁵Mto 3.10⁻⁹M. From the thus obtained dose response curves, the pIC50 valuewas calculated and scored as follows; Score 1=pIC50 value<5, Score2=pIC50 value in the range of 5 to 6, Score 3=pIC50 value>6. Some of thethus obtained results are summarized in the table below. (in this tableNT stands for Not Tested).

Example C2 Cellular Assays to Test the Effect of Compounds on11b-Hydroxysteroid Dehydrogenase Type 1 and Type 2

The effects on 11b-HSD1 activity was measured in differentiated 3T3-L1cells and rat hepatocytes.

Mouse fibroblast 3T3-L1 cells (ATCC-CL-173) were seeded at a density of16500 cells/ml in 12 well plates and grown for 7 days in DMEM medium(supplemented with 10% heat inactivated foetal calf serum, 2 mMglutamine and 25 mg gentamycin) at 37 C in a humidified 5% CO2atmosphere. Medium was refreshed twice a week. Fibroblasts weredifferentiated into adipocytes at 37 C in a 5% CO2 humidified atmospherein growth medium containing 2 μg/ml insulin, 55 μg/ml IBMX and 39.2μg/ml dexamethasone.

Primary hepatocytes from male rats were seeded on BD-Biocoat Matrigelmatrix multiwell plates at a density of 250000 cells/well and incubatedfor 10 days at 37 C in a 5% CO2 humidified atmosphere in DMEM-HAM's F12medium containing 5% Nu-serum, 100 U/ml penicillin, 100 μg/mlstreptomycin, 0.25 μg/ml amphotericin B, 50 μg/ml gentamycin sulfate, 5μg/ml insulin and 392 ng/ml dexamethasone. Medium was refreshed 3 timesa week.

Following a 4 hour pre-incubation with test compound, 0.5 μCi³H-cortisone or dehydrocorticosterone, was added to the cultures. Onehour later, the medium was extracted on Extrelut³-columns with 15 mldiethyl ether and the extract was analysed by HPLC as described above.

The effects on 11b-HSD2 activity was studied in HepG2 and LCC-PK1-cellsHepG2-cells (ATCC HB-8065) were seeded in 12 well plates at a density of100,000 cells/ml and grown at 37 C in a humidified 5% CO2 atmosphere inMEM-Rega-3 medium supplemented with 10% heat inactivated foetal calfserum, 2 mM L-glutamine and sodium bicarbonate). Medium was refreshedtwice a week.

Pig kidney cells (LCC-PK1, ATCC CRL-1392) were seeded at a density of150,000 cells/ml in 12 well plates and grown at 37 C in a humidified 5%CO2 atmosphere in Medium 199 supplemented with Earls modified saltsolution, 100 U/ml penicillin, 100 μg/ml streptomycin and 10% foetalcalf serum. Medium was refreshed twice a week. Twenty four hours priorto the onset of the experiment, medium was changed by medium containing10% charcoal stripped foetal calf serum.

Following a 4 hour pre-incubation with test compound, 0.5 μCi³H-cortisol or corticosterone, was added to the cultures. One hourlater, the medium was extracted on Extrelut³-columns with 15 ml diethylether and the extract was analysed by HPLC as described above.

As for the enzymatic assays, the compounds to be tested were taken froma stock solution and tested at a final concentration ranging from −10⁻⁵Mto 3.10⁻⁹M. From the thus obtained dose response curves, the pIC50 valuewas calculated and scored as follows; Score 1=pIC50 value<5, Score2=pIC50 value in the range of 5 to 6, Score 3=pIC50 value>6. Some of thethus obtained results are summarized in the table below (in this tableNT stands for Not Tested).

[C1] [C2] HSD2 HSD1-prot [C1] HSD2 [C2] HSD1 cellular Compound Reductprot Dehydro cellular 3T3-L1 HepG2 Number Score Score Score Score 1 3 13 1 2 2 NT 2 1 3 3 NT 2 1 4 1 NT 2 1 5 2 NT 2 1 6 2 NT 2 1 7 2 1 3 1 8 2NT 2 NT 9 2 1 3 1 10 3 1 3 1 11 3 NT 2 NT 12 2 NT 2 NT 13 3 1 3 1 14 3 13 1 15 2 NT 2 NT 16 1 NT 2 NT 17 2 NT 2 NT 18 2 NT 2 NT 19 2 NT 3 NT 201 NT 1 NT 21 2 NT 3 NT 22 1 NT 2 NT 23 2 NT 3 NT 24 2 NT 1 NT 25 1 NT 3NT 26 1 NT 2 NT 27 1 1 3 1 28 1 1 3 1 29 2 NT 2 NT 30 3 1 3 1 31 2 1 3 132 3 1 3 1 33 1 NT 3 NT 34 1 NT 2 NT 35 1 1 3 1 36 1 NT 2 NT 37 1 NT 2NT 38 1 NT 2 NT 39 1 NT 2 NT 40 2 NT 3 NT 41 2 1 3 1 42 1 NT 2 NT 43 2NT 2 NT 44 1 NT 2 NT 45 3 1 3 1 46 1 NT 1 NT 47 1 NT 2 NT 48 1 NT 2 NT49 2 NT 3 NT 50 1 NT 2 NT 51 1 NT 2 NT 52 1 NT 2 NT 53 1 NT 2 NT 54 1 NT2 NT 55 1 NT 2 NT 56 1 NT 2 NT 57 2 1 3 1 58 2 NT 2 NT 59 2 1 3 1 60 1NT 2 NT 61 1 NT 2 NT 62 1 NT 2 NT 63 1 NT 2 NT 64 1 NT 2 NT 65 1 1 3 166 1 NT 2 NT 67 2 NT 3 NT 68 1 NT 2 NT 69 2 NT 3 1 70 1 NT 3 1 71 3 NT 31 72 1 NT 2 NT 73 3 NT 2 NT 74 2 NT 2 NT 75 3 NT 2 NT 76 3 NT 2 NT 77 3NT 3 1 78 3 NT 3 NT 79 3 NT 3 NT 80 3 NT 3 1 81 1 NT 3 NT 82 3 NT 2 NT83 3 NT 1 NT 84 2 NT 3 NT 85 2 NT 1 NT 86 2 NT 3 NT 87 1 NT 2 NT 88 2 NT2 NT 89 1 NT 2 NT 90 1 NT 2 NT 91 2 NT 3 NT 92 3 NT 2 NT 93 1 NT 1 NT 941 NT 3 NT 95 3 NT 2 NT 96 2 NT 1 NT 97 3 2 1 1 98 1 NT 2 NT 99 3 NT 3 NT100 2 NT 1 NT 101 1 NT 1 NT 102 1 NT 1 NT 103 1 NT 1 NT 104 1 NT 2 NT105 3 NT 3 NT 106 2 NT 1 NT 107 2 NT 1 NT 108 2 NT 2 NT 109 1 NT 2 NT110 2 NT 2 NT 111 2 NT 2 NT 112 2 NT 2 NT 113 2 NT 2 NT 114 1 NT 3 NT115 1 NT 3 NT 116 1 NT 1 NT 117 3 NT 3 NT 118 1 NT 2 NT 119 3 2 3 1 1202 NT 3 NT 121 1 NT 1 NT 122 2 NT 2 NT 123 2 NT 2 NT 124 2 NT 2 NT 125 1NT 1 NT 126 1 NT 1 NT 127 2 NT 2 NT 128 2 NT 2 NT 129 2 NT 2 NT 130 1 NT2 NT 131 1 NT 2 NT 132 2 NT 2 NT 133 1 NT 2 NT 134 3 NT 3 NT 135 1 NT 3NT 136 2 NT 2 NT 137 3 NT 3 NT 138 2 NT 2 NT 139 3 NT 3 NT 140 1 NT 3 NT141 3 NT 1 NT 142 1 NT 2 NT 143 1 NT 2 NT 144 1 NT 1 NT 145 1 NT 1 NT146 1 NT 1 NT 147 1 NT 1 NT 148 1 NT 3 1 149 1 NT 3 1 150 3 NT 3 NT 1513 NT 3 NT 152 2 NT 3 NT 153 2 NT 2 NT 154 1 NT 3 2 155 3 NT 3 NT 156 2NT 2 NT 157 2 NT 3 NT 158 3 NT 3 NT 159 3 NT 3 NT 160 3 NT 1 NT 161 2 NT1 NT 162 3 2 3 1 163 3 2 3 1 164 1 NT 1 NT 165 1 NT 1 NT 166 NT NT 2 NT167 NT NT 1 NT

D. Composition Examples

The following formulations exemplify typical pharmaceutical compositionssuitable for systemic or topical administration to animal and humansubjects in accordance with the present invention.

“Active ingredient” (A.I.) as used throughout these examples relates toa compound of formula (I) or a pharmaceutically acceptable addition saltthereof.

Example D.1 Film-Coated Tablets Preparation of Tablet Core

A mixture of A.I. (100 g), lactose (570 g) and starch (200 g) was mixedwell and thereafter humidified with a solution of sodium dodecyl sulfate(5 g) and polyvinyl-pyrrolidone (10 g) in about 200 ml of water. The wetpowder mixture was sieved, dried and sieved again. Then there was addedmicrocrystalline cellulose (100 g) and hydrogenated vegetable oil (15g). The whole was mixed well and compressed into tablets, giving 10.000tablets, each comprising 10 mg of the active ingredient.

Coating

To a solution of methyl cellulose (10 g) in denaturated ethanol (75 ml)there was added a solution of ethyl cellulose (5 g) in CH₂Cl₂ (150 ml).Then there were added CH₂Cl₂ (75 ml) and 1,2,3-propanetriol (2.5 ml).Polyethylene glycol (10 g) was molten and dissolved in dichloromethane(75 ml). The latter solution was added to the former and then there wereadded magnesium octadecanoate (2.5 g), polyvinyl-pyrrolidone (5 g) andconcentrated color suspension (30 ml) and the whole was homogenated. Thetablet cores were coated with the thus obtained mixture in a coatingapparatus.

1. A compound having the formula

the N-oxide forms, the pharmaceutically acceptable addition salts andthe stereochemically isomeric forms thereof, wherein n is 2; Lrepresents a C₁₋₃alkyl linker optionally substituted with one or twosubstituents selected from C₁₋₄alkyl, C₁₋₃-alkyloxy-C₁₋₄alkyl-,hydroxy-C₁₋₄alkyl, hydroxy, C₁₋₃alkyloxy- or phenyl-C₁₋₄alkyl; Mrepresents a direct bond or a C₁₋₃alkyl linker optionally substitutedwith one or two substituents selected from hydroxy, C₁₋₄alkyl orC₁₋₄alkyloxy; R¹ and R² each independently represent hydrogen, halo,cyano, hydroxy, C₁₋₄alkyl optionally substituted with halo,C₁₋₄alkyloxy- optionally substituted with one or where possible two orthree substituents selected from hydroxy, Ar¹ and halo; or R¹ and R²taken together with the phenyl ring to which they are attached formnaphtyl or 1,3-benzodioxolyl, wherein said naphtyl or 1,3-benzodioxolylare optionally substituted with halo; R³ represents hydrogen, halo,C₁₋₄alkyl, C₁₋₄alkyloxy-, cyano or hydroxy; R⁴ represents hydrogen,halo, C₁₋₄alkyl, C₁₋₄alkyloxy-, cyano or hydroxy; R⁵ representshydrogen, C₁₋₄alkyl or Ar²—C₁₋₄alkyl-; R⁶ represents hydrogen, halo,C₁₋₄alkyl or C₁₋₄alkyoxy-; Ar¹ and Ar² each independently representphenyl or naphtyl wherein said phenyl and naphtyl are optionallysubstituted with C₁₋₄alkyl, C₁₋₄alkyloxy-, or phenyl-C₁₋₄alkyl; for useas a medicine.
 2. A compound according to claim 1 wherein; n is 2; Lrepresents a C₁₋₃alkyl linker optionally substituted with one or twosubstituents selected from C₁₋₄alkyl, C₁₋₃alkyloxy-C₁₋₄alkyl-,hydroxy-C₁₋₄alkyl, hydroxy, C₁₋₃alkyloxy- or phenyl-C₁₋₄alkyl; inparticular L represents a C₁-linker optionally substituted withC₁₋₄alkyl; preferably L represents a C₁-linker substituted withC₁₋₄alkyl, more preferably a C₁-linker substituted with methyl; Mrepresents a direct bond or a C₁₋₂alkyl optionally substituted with oneor two substituents selected from hydroxy, C₁₋₄alkyl or C₁₋₄alkyloxy-;preferably M represents a C₁-linker optionally substituted withC₁₋₄alkyl; R¹ represents hydrogen, hydroxy, halo, C₁₋₄alkyl,C₁₋₄alkyloxy-, or C₁₋₄alkyloxy substituted with halo; R² representshydrogen, halo, C₁₋₄alkyl, C₁₋₄alkyloxy- or Ar¹—C₁₋₄alkyloxy-; R³represents hydrogen, halo, C₁₋₄alkyl, C₁₋₄alkyloxy- or cyano; R⁴represents hydrogen, halo, C₁₋₄alkyl or C₁₋₄alkyloxy-; R⁵ representshydrogen, C₁₋₄alkyl or Ar²—C₁₋₄alkyl; in particular hydrogen; R⁶represents hydrogen, halo, or C₁₋₄alkyloxy; in particular hydrogen,chloro, fluoro, bromo or methoxy; Ar¹ represents phenyl; Ar² representsphenyl or naphtyl.
 3. (canceled)
 4. A compound according to claim 1wherein R⁶ is at the para position, L represents a C₂-alkyl linker and Mrepresents a C₁-linker.
 5. A compound according to claim 1 wherein Lrepresents a C₁-linker substituted with a C₁₋₄alkyl,C₁₋₄alkyloxyC₁₋₄alkyl-, hydroxyC₁₋₄alkyl- or phenylC₁₋₄alkyl- whereinsaid C₁₋₄alkyl, C₁₋₄alkyloxyC₁₋₄alkyl-, hydroxyC₁₋₄alkyl- orphenylC₁₋₄alkyl- is in the S-configuration.
 6. (canceled)
 7. Apharmaceutical composition comprising a pharmaceutically acceptablecarrier and, as active ingredient, an effective 11β-HSD1 inhibitoryamount of a compound as described in any one of claim
 1. 8. A process ofpreparing a pharmaceutical composition as defined in claim 7,characterized in that, a pharmaceutically acceptable carrier isintimately mixed with an effective 11β-HSD1 inhibitory amount of acompound as described in any one of claim
 1. 9. (canceled)
 10. A methodfor treating pathologies associated with excess cortisol formation,comprising administering an effective amount of a compound as claimed inclaim
 1. 11. The method of claim 10, wherein the pathology associatedwith excess cortisol formation is selected from obesity, diabetes,obesity related cardiovascular diseases, dementia, cognition,osteoporosis and glaucoma.